KR20070116645A - Novel thiophene derivatives as sphingosine-1-phosphate-1 receptor agonists - Google Patents

Abstract

The invention relates to novel thiophene derivatives of formula (l), their preparation and their use as pharmaceutically active compounds. Said compounds particulary act as immunosuppressive agents. wherein ring A represents oxadiazole and the other substituents are as defined in the description.

Description

Novel thiophene derivatives as sphingosine-1-phosphate-1 receptor antagonists {NOVEL THIOPHENE DERIVATIVES AS SPHINGOSINE-1-PHOSPHATE-1 RECEPTOR AGONISTS}

Field of invention

The present invention relates to the S1P1 / EDG1 receptor agonists of formula (I) and their use as active ingredients in the preparation of pharmaceutical compositions. The present invention also provides methods of preparing the compounds, pharmaceutical compositions containing the compounds of formula (I), and compounds which improve vascular function and as immunomodulatory agents, alone or in combination with other compounds or therapies Consider relevant aspects including the use of.

Background of the Invention

The human immune system is designed to defend the body against foreign microbes and substances that cause infection or disease. Complex regulatory mechanisms allow the immune response to be targeted against invading substances or organisms, not against the host. In some cases, this control mechanism is not regulated and autoimmune responses can develop. Uncontrolled inflammatory reactions result in serious organ, cell, tissue, or connective tissue damage. In current treatments, all immune systems are usually suppressed and the body's ability to respond to infection is also severely impaired. Typical drugs in this case include azathioprine, chlorambucil, cyclophosphamide, cyclosporin, or methotrexate. Corticosteroids that reduce inflammation and suppress the immune response can cause side effects when used for long-term treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and salts, but they have serious side effects. Alternative treatments include agents that activate or block cytokine signals.

Oral active compounds that have immunomodulatory properties, do not compromise the immune response, and reduce side effects will significantly improve the current treatment of uncontrolled inflammatory diseases.

In the field of organ transplantation, host immune responses must be suppressed to prevent organ rejection. Organ transplant recipients may experience some rejection even when taking immunosuppressive drugs. Rejection reactions occur most frequently in the first weeks after transplantation, but rejection episodes may occur for months or years after transplantation. Combinations of up to three or four agents are commonly used to provide maximum protection against rejection while minimizing side effects. Current standard drugs used to treat rejection of transplanted organs interfere with discontinuous intracellular pathways in the activation of T-type or B-type leukocytes. Examples of such drugs include cyclosporin, daclizumab, basiliximab, erollimus, or FK506 that interfere with cytokine release or signaling; Azathioprine or leflunomide that inhibits nucleotide synthesis; Or 15-deoxyspergualin, an inhibitor of leucosite differentiation.

The beneficial effects of a wide range of immunosuppressive therapies relate to their effects; However, the generalized immunosuppression produced by these drugs reduces the immune system's defense against infection and malignancy. Moreover, standard immunosuppressive drugs are often used in high doses and can cause or accelerate organ damage.

Description of the Invention

The present invention has a potent and long lasting immunosuppressive effect achieved by reducing the number of circulating and penetrating T- and B-lymphocytes without affecting their maturation, memory, or dilator, G protein-bound Provided are novel compounds of formula (I) that are agonists for receptor S1P1 / EDG1. As a result of S1P1 / EDG1 efficacy, a decrease in circulating T- / B-lymphocytes, combined with an improvement in endothelial cell layer function associated with S1P1 / EDG1 activation, has led to these compounds treating uncontrolled inflammatory diseases and vascular function. Useful to improve.

The compounds of the present invention can be used alone or in combination with standard drugs that inhibit T-cell activation to provide novel immunosuppressive therapies that reduce the propensity to infection as compared to standard immunosuppressive treatments. Moreover, the compounds of the present invention are reduced on the one hand to provide effective immunosuppressive activity and, on the other hand, to reduce terminal organ damage associated with using higher doses of standard immunosuppressive drugs. It can be used in combination with using a dose of a traditional immunosuppressive therapeutic. Observation of improved endothelial cell layer function associated with S1P1 / EDG1 activation provides additional benefits of the compound for improving vascular function.

Nucleotide and amino acid sequences for human S1P1 / EDG1 receptors are known in the art, such as T., and Maciag, T. J. Biol Chem . 265 (1990), 9308-9313; WO 91/15583, published October 17, 1991; WO 99/46277, published September 16, 1999. The efficacy and efficacy of the compounds of formula (I) are each evaluated by determining EC ₅₀ values using GTPS analysis and measuring lymphocytes circulating in mice after oral administration (see Examples).

The following paragraphs provide definitions of the various chemical components that make up the compounds according to the present invention, which definitions apply equally throughout the specification and claims, unless a broader definition is provided in a manner different from that described. will be.

Alone or a C _{1 -5} in combination with other groups - to a saturated branched or terms having one to five carbon atoms, preferably 1 to 3 carbon atoms of the alkyl preferably refers to a straight-chain group. C _{1 -5} - Examples of alkyl groups are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and n- pentyl.

Alone or in combination with other groups, C _{1 -5} for use - the term alkoxy means an RO group, wherein R is C _{1 -5-alkyl.} C _{1 -5} - Preferred examples of the alkoxy group are methoxy, ethoxy, propoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy it is.

Alone or hydroxyalkyl -C _{2 -5} are used in combination with other groups, - the term alkoxy means a straight or branched alkoxy chain having an hydroxy group and, whereby hydroxy groups and C _{2 -5-alkoxy} group There are at least two carbon atoms between the oxygens. Hydroxyalkyl -C _{2 -5} - Examples of alkoxy groups are 2-hydroxy-ethoxy, 3-hydroxy-propoxy, 2-hydroxy-propoxy, 4-hydroxy-butoxy, 3-hydroxy - 1-methyl-propoxy, 3-hydroxy-butoxy, and the like.

Mono- or di (C _1-5 - alkyl) amino term are each R'-NH- or a R'-NR '' - meaning a group, where R 'and R''are independently C _{1 -5,} respectively -Alkyl group. Mono-or di - (C _{1 -5-alkyl)} Preferred examples of the amino group are methylamino, ethylamino, N, N- dimethylamino, and N- methyl -N- ethyl-amino.

The term halogen means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

As used herein, the plural forms are used with reference to compounds, salts, pharmaceutical compositions, diseases, and the like, which is intended to also mean one compound, salt, and the like.

References to the compounds of formula (I) described above or below refer to optically pure enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and diastereomeric racemates Mixtures of enantiomers, such as mixtures of sieves, and coordination isomers such as salts of these compounds (especially pharmaceutically acceptable salts) and solvent complexes (including hydrates), and appropriate and suitable morphological forms. It must be understood.

Salts are preferably pharmaceutically acceptable salts of compounds of formula (I).

Salt-forming groups are basic or acidic groups or radicals. For example, a compound having at least one basic group or at least one basic radical, or pyridyl radical, such as amino, secondary amino group, which does not form a peptide bond, forms an acid addition salt with, for example, an inorganic acid. can do. When several basic groups are present, mono- or poly-acid addition salts can be formed.

Compounds having acidic groups such as carboxyl groups or phenolic hydroxy groups are alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts or ammonia or tertiary monoamines such as triethylamine Or metal or ammonium salts such as ammonium salts with suitable organic amines such as tri- (2-hydroxyethyl) -amine, or for example N-ethyl-piperidine or N, N' -dimethylpiperazine; The same heterocyclic base can be formed. Mixtures of salts are also possible.

Compounds having acidic and basic groups can form internal salts. It is also possible to use pharmaceutically unacceptable salts such as, for example, picric acid, for the purpose of separation or purification, and for compounds further used as intermediates. However, only pharmaceutically acceptable, non-toxic salts can be used for therapeutic purposes and these salts are therefore preferred.

The term pharmaceutically acceptable salts refers to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, phosphorous acid, nitrous acid, citric acid, formic acid, acetic acid, oxalic acid, maleic acid, lactic acid, tartaric acid, which are nontoxic to living organisms. , Fumaric acid, benzoic acid, mandelic acid, cinnamic acid, pamoic acid, stearic acid, glutamic acid, aspartic acid, methanesulphonic acid, ethanedisulphonic acid, p-toluenesulphonic acid, salicylic acid Salts with inorganic or organic acids, such as succinic acid, trifluoroacetic acid, or the like, or in the case of compounds of formula (I), essentially, for example, inorganic such as alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. Acidic with sex base. Other examples of pharmaceutically acceptable salts are described in “Salt selection for basic drugs”, Int. J. Pharm. (1986), 33,201-217.

The compound of formula (I) may contain asymmetric carbon atoms. Substituents in a double bond or a ring may be present in cis- (= Z-) or trans (= E-) form unless otherwise indicated. The compounds of formula (I) may therefore exist as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a known manner such as, for example, by column chromatography, thin layer chromatography, HPLC or crystallization.

i) The present invention relates to novel thiophene derivatives of formula (I) and optically pure enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and diastereoisomers Mixtures of enantiomers, such as mixtures of racemates, and coordination isomers such as salt and solvent complexes, and morphological forms of these compounds;

Formula (I)

here

Ring A is

Indicates,

R ¹ represents hydrogen, lower alkyl, lower alkoxy, or halogen;

R ² represents hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, or halogen;

R ³ is hydrogen, hydroxy-lower alkyl, 2,3-dihydroxypropyl, di- (hydroxy-lower alkyl) -lower alkyl, -CH _2- (CH ₂ ) _k -NR ³¹ R ³² , (Aze Thidin-3-carboxylic acid) -1-yl-methyl, (azetidine-3-carboxylic acid lower alkyl ester) -1-yl-methyl, 2-[(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2-[(azetidine-3-carboxylic acid lower alkyl ester) -1-yl] -ethyl, 3-[(azetidine-3-carboxylic acid) -1-yl] -propyl, 3-[(azetidine-3- Carboxylic acid lower alkyl ester) -1-yl] -propyl, (pyrrolidin-3-carboxylic acid) -1-yl-methyl, (pyrrolidine-3-carboxylic acid lower alkyl ester) -1-yl-methyl, (pi Ralidin-2-carboxylic acid) -1-yl-methyl, (pyrrolidin-2-carboxylic acid lower alkyl ester) -1-yl-methyl, 2-[(pyrrolidine-3-carboxylic acid) -1-yl] -Ethyl, 2-[(pyrrolidin-3-carboxylic acid lower alkyl ester) -1-yl] -ethyl, 2-[(pyrrolidine-2-carboxylic acid) -1-yl] -ethyl, 2-[( Pyrroly 2-carboxylic acid lower alkyl ester) -1-yl] -ethyl, 3-[(pyrrolidine-3-carboxylic acid) -1-yl] -propyl, 3-[(pyrrolidine-3-carboxylic acid lower alkyl ester ) -1-yl] -propyl, 3-[(pyrrolidin-2-carboxylic acid) -1-yl] -propyl, 3-[(pyrrolidine-2-carboxylic acid lower alkyl ester) -1-yl]- Propyl, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CO-NHR ³¹ , (CH ₂ ) _n CH (OH) -CH ₂ -NR ³¹ R ³² , hydroxy, lower alkoxy, fluoro- Lower alkoxy, hydroxy-lower alkoxy, di- (hydroxy-lower alkyl) -lower alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH _2- ( CH ₂ ) _m- NR ³¹ R ³² , 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (Lower alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1 -Yl-propoxy, 3- [4- (lower alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2 -Hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[(azetidine-3 -Carboxylic acid) -1-yl] -ethoxy, 2-[(azetidine-3-carboxylic acid lower alkyl ester) -1-yl] -ethoxy, 2-[(pyrrolidine-3-carboxylic acid) -1- Il] -ethoxy, 2-[(pyrrolidine-3-carboxylic acid lower alkyl ester) -1-yl] -ethoxy, 2-[(pyrrolidine-2-carboxylic acid) -1-yl] -ethoxy , 2-[(pyrrolidine-2-carboxylic acid lower alkyl ester) -1-yl] -ethoxy, 2-[(2-hydroxy-pyrrolidin) -1-yl] -ethoxy, 2- [ (3-hydroxy-pyrrolidin) -1-yl] -ethoxy, 3-[(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(azetidine-3-carboxylic acid lower) Alkyl ester) -1-yl] -propoxy, 3-[(pyrrolidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(pyrrolidine-3-carboxylic acid lower alkyl ester) -1 -Yl] -propoxy, 3-[(pyrrolidin-2-carboxylic acid) -1-yl] -propoxy, 3-[(pyrrolidine-2-carboxylic acid lower alkyl ester) -1-yl] -propoxy, 3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 3-[( 3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -O-CH ₂ -CONR ³¹ R ³² , 3-carr Barmoyl-propoxy, 3- (lower alkylcarbamoyl) propoxy, 3- (2-hydroxyethylcarbamoyl) propoxy, OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , 3 -[(Azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3-[(azetidine-3-carboxylic acid lower alkyl ester) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid lower alkyl ester) -1-yl ] -Propoxy, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid lower alkylester ) -1-yl] -propoxy, 2-hydroxy-3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -Propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- ( Lower alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy- 3-morpholin-4-yl-propoxy, -NR ³¹ R ³² , -NHCO-R ³¹ , -CH _2- (CH ₂ ) _k -NHSO ₂ R ³³ ,-(CH ₂ ) _n CH (OH)- ^{_{CH 2 -NHSO 2 R 33, -OCH}} 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2) k - NHCOR ³⁴ , (CH ₂ ) _n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m -NHCOR ³⁴ , or -OCH ₂ -CH (OH) -CH ₂ -NHCOR ³⁴ ;

R ³¹ is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethyl-ethyl, 2-lower alkoxyethyl, 3-hydroxypropyl, 3- Lower alkoxypropyl, 2-aminoethyl, 2- (lower alkylamino) ethyl, 2- (di- (lower alkyl) amino) ethyl, carboxymethyl, lower alkylcarboxymethyl, 2-carboxyethyl, or 2- (lower alkyl Carboxy) ethyl;

R ³² represents hydrogen, methyl, or ethyl;

R ³³ represents methyl, ethyl, propyl, isopropyl, butyl, 2-hydroxyethyl, 2methoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, nbutylamino, or dimethylamino;

R ³⁴ represents hydroxymethyl, hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, 2-methylamino-ethyl, or 2-dimethylamino-ethyl;

k represents the integer 1, 2, or 3;

m represents an integer of 1 or 2;

n represents 0, 1, or 2;

R ⁴ represents hydrogen, lower alkyl, or halogen.

ii) specific embodiments of the present invention in relation to thiophene derivatives according to embodiment i), wherein R ³ is hydrogen, hydroxy -C _{1 -5-alkyl,} 2,3-dihydroxy-propyl, di- ( _-5-hydroxy-1 -C-alkyl) -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1-yl-methyl, (azetidine tidin-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [(azetidine tidin-3-carboxylic acid) -1-yl] -ethyl, 2 - [(azetidine-3-carboxylic acid C tidin _1-5-alkyl ester) -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _1-5 -alkyl ester) 1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, ( pyrrolidone-2-carboxylic acid) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2- [(pyrrolidine-3-carboxylic acid pi) -1-yl] -ethyl, 2-[(pyrrolidin-3-car Reubok acids C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _1-5-alkyl ester) -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidine-3-carboxylic acid C _1-5 pie - alkylester) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkyl} ester ) -1-yl] -propyl, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CO-NHR ³¹ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NR ³¹ R ³² , Hydro hydroxy, C _{1 -5-alkyl,} -C _{1 -5;} fluoro-alkoxy, hydroxy -C _{2 -5-alkoxy,} di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5} - alkoxy, 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH _2- (CH ₂ ) _m -NR ³¹ R ³² , 2-pyrrolidin-1-yl-ethoxy , 3-pyrrolidone-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -ethoxy , 2- [4- (2-hydr City-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] - Propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-prop propoxy, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2- [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2- [ (2-hydroxy-pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -ethoxy, 3-[(azetidine-3- carboxylic acid) -1-yl] -propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidine-3-carboxylic acid pi) -1-yl] -propoxy , 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -0-CH ₂ -CONR ³¹ R ³² , 3-carbamoyl-propoxy, 3- (C _1-5 -alkylcarbamoyl) propoxy, 3- (2-hydroxyethylcarbamoyl) propoxy, -OCH ₂ -CH (OH)- _{^{CH 2 -NR 31 R 32, 3}} - [( azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkyl} ester) -1-yl] -2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidin-3-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrroli -3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(par Pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3- [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2 -Hydroxy-3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl]- Propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C _1-5-alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2- Hydroxy-3-morpholin-4-yl-propoxy, -NR ³¹ R ³² , -NHCO-R ³¹ , -CH _2- (CH ₂ ) _k -NHSO ₂ R ³³ ,-(CH ₂ ) _n CH ( ^{_{OH) -CH 2 -NHSO 2 R 33}} , -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 -NHSO 2 R 33, -CH 2 - (CH 2 ) _k -NHCOR ³⁴ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m -NHCOR ³⁴ , or -OCH ₂ -CH (OH) -CH ₂ -NHCOR ³⁴ represents, and R ³¹ , R ³² , R ³³ and R ³⁴ are the above specific examples; as defined in i).

iii) Specific embodiments of the invention relate to thiophene derivatives according to embodiment i) or ii), wherein the compounds represented by formula (I) are 1,1,2-trimethyl-1,1a, 5, It constitutes the (1aR, 5aS) -isomer of the 5a-tetrahydro-3-thia-cyclopropa [a] pentalene derivative.

iv) Preferred embodiments of the invention relate to thiophene derivatives according to embodiment i) or ii), wherein the compounds represented by formula (I) are 1,1,2-trimethyl-1,1a, 5,5a -Constitute the (1aS, 5aR) -isomer of tetrahydro-3-thia-cyclopropa [a] pentalene.

v) Preferred embodiments of the invention relate to thiophene derivatives according to any one of embodiments i) to iv) wherein the compounds represented by formula (I) are 5-thiophen-2-yl- [1, 2,4] oxadiazole derivatives.

vi) Another preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) to iv) wherein the compounds represented by formula (I) are 3-thiophen-2-yl- [ 1,2,4] oxadiazole derivatives.

vii) Preferred embodiments of the invention relate to thiophene derivatives according to any one of embodiments i) to vi), wherein R ¹ , R ² , and R ⁴ represent hydrogen.

viii) Another preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) to vi), wherein R ¹ represents hydrogen and R ² and R ⁴ represent methyl groups.

ix) Another preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) to vi), wherein R ¹ represents hydrogen, R ² represents a methyl group and R ⁴ represents an ethyl group Indicates.

x) Another preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) to vi), wherein R ¹ represents hydrogen, R ² represents a methoxy group and R ⁴ is chlorine Indicates.

xi) in relation to thiophene derivatives according to any one of the alternative embodiments of the present invention are embodiments i) to x), wherein R ³ is hydrogen, hydroxy -C _{1 -5} - alkyl, 2,3- hydroxypropyl, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1 -yl-methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [( azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidin-3 acid C _{1 -5-alkylester)} -1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkyl} ester) 1- yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [(pi Ralidin-3-carboxylic acid) -1-yl] -ethyl 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [(pi pyrrolidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pi pyrrolidine- 2-carboxylic acid C _{1 -5-alkylester)} -1-yl] _{-propyl, -CH 2 - (CH 2)} n -CONR 31 R 32, -CO-NHR 31, - (CH 2) n CH (OH) -CH ₂ -NR ³¹ R ^32, hydroxy, C _{1 -5-alkyl,} -C _{1 fluoroalkyl-5-alkoxy,} hydroxy ₂ -C ₅ - alkoxy, di- (hydroxy -C _1-5 - alkyl) -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, _{2-hydroxy-3-methoxy-propoxy, -OCH 2 - (CH 2)} m -NR 31 R 32, 2- pyrrolidone-1-yl-ethoxy, 3-pyrrolidone-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C _{1 -5-alkyl)} - Piperazin-1-yl] -on When, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy, 3- [4- (C _{1 -5-} Alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy , 3-morpholine-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2- [(azetidine-3-carboxylic acid C _{1 -5-alkyl} ester ) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkyl} ester) 1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkyl} ester) 1-yl] -ethoxy, 2-[(2-hydroxy-pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl]- Methoxy, 3-[(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(azetidine-3-carboxylic acid C _1-5 -alkylester) -1-yl] -propoxy, 3 -[(Pyrrolidine-3-carboxy Acid) -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid ) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy-pi pyrrolidine ) -1-yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, _{^{-0-CH 2 -CONR 31 R 32}} , 3- carbamoyl-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxyethyl carbamoyl) propoxy , -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , 3-[(azetidin-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3-[(azetidine-3 - carboxylic acid C _{1 -5-alkylester)} -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propoxy, 2 -hydroxy-3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3- [(pyrrolidone-2-carboxylic acid C _{1 -5-alkyl} ester) -1-yl] -propoxy, 2-hydroxy-3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-[(3-hydroxy- Pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1-yl-propoxy, 2- hydroxy-3- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin- 1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, or -NR ³¹ R ³² , -NHCO-R ³¹ and R ³¹ and R ³² are embodiments i) As defined in.

xii) Another embodiment of the present invention are embodiments i) and iii) to x) of the in relation to thiophene derivatives according to any one, in which R ³ is hydrogen, hydroxy -C _{1 -5} - alkyl, 2, 3-di-hydroxypropyl, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkyl,} -CH2- (CH2) k-NR 31 R 32, ( azetidine-3-carboxylic acid) 1- yl-methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2- [ (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine -3 - carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkyl} ester) 1-yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [( Pyrrolidin-3-carboxylic acid) -1-yl]- Butyl, 2- [(pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [( pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pi pyrrolidine -2-carboxylic acid C _1-5 -alkylester) -1-yl] -propyl, -CH _2- (CH ₂ ) _n -COOH, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CO- _{^{NHR 31, - (CH 2)}} n CH (OH) -CH 2 -NR 31 R 32, hydroxy, C _{1 -5} - alkoxy, fluoro -C _{1 -5} - alkoxy, hydroxy, -C _{2 -5} - alkoxy, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH ₂ - (CH ₂ ) _m -NR ³¹ R ³² , 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2 - [4- (C _{1 -5} - Kiel) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl-propoxy 3- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] propoxy , 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[(azetidin-3-carboxylic acid) -1-yl] -ethoxy, 2- [ tidin-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pi pyrrolidine 3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pi pyrrolidine- 2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(2-hydroxy-pi pyrrolidine) -1-yl] -ethoxy, 2 - [(3-hydroxy pi-pyrrolidine) -1-yl] -ethoxy, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkyl} Ester) -1-yl] -propoxy, 3- [ (Pi pyrrolidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [( pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2 -Hydroxy-pyrrolidin) -1-yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2- hydroxymethyl-propoxy, -0-CH ₂ -CONR ³¹ R ^32, 3-carbamoyl-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxy Ethylcarbamoyl) propoxy, -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , 3-[(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid) -1 yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkyl} Ter) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine- 2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 2-hydroxy Hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-pipe piperazine-1 - yl-propoxy, 2-hydroxy-3- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- ( 2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, or -NR ³¹ R ³² , -NHCO-R ³¹ Wherein R ³¹ and R ³² are as defined in embodiment i) above.

xiii) in relation to thiophene derivatives according to any one of another preferred embodiment of the present invention are embodiments i) to x), wherein R ³ is hydroxy _-5 -C ₂ - alkoxy, di- (hydroxy- C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, _{2-hydroxy-3-methoxy-propoxy, -OCH 2 - (CH 2)} m -NR 31 R ^32, 2-pyrrolidone-1-yl-ethoxy, 3-pyrrolidone-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C _{1 - 5} -alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl- Propoxy, 3- [4- (Ci_ ₅ -alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl]- Propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[(azetidin-3-carboxylic acid) -1-yl] -ethoxy, 2- [ (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] ethoxy 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(2-hydroxy-pi pyrrolidine) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -ethoxy, 3-[(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(azetidine-3 - carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidine-3-pi acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 3 - [(3-hydroxy-pyrrolidone Dean) -1-yl] -propoxy, ^{_{2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -0-CH 2 -CONR 31 R}} 32, 3- carboxylic Gather-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxyethyl carbamoyl) _{propoxy, -OCH 2 -CH (OH) -CH} 2 -NR 31 R ^32, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] 2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pi pyrrolidine) -1-yl] - Propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2- hydroxy-3-piperazin-1-yl-propoxy, 2-hydroxy-3- [4- (C _{1 -5-Al} Kiel) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, or 2-hydroxy- 3-morpholin-4-yl-propoxy and R ³¹ and R ³² are as defined in embodiment i) above.

xiv) in relation to thiophene derivatives according to any one of the alternative embodiments of the present invention are embodiments i) to x), wherein R ³ is hydroxy -C _{1 -5} - alkyl, 2,3-dihydroxy propyl, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1-yl -methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [(azetidine 3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _1-5-alkyl ester) -1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _1-5 -alkyl ester) -1 yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [(pi pyrrolidine -3-carboxylic acid) -1-yl] -ethyl, 2-[( It is pyrrolidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pi pyrrolidine 2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidine-3-pi acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5} -alkylester) -1-yl] -propyl, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CO-NHR ³¹ , or-(CH ₂ ) _n CH (OH) -CH _2- NR ³¹ R ³² and R ³¹ and R ³² are as defined in embodiment i) above.

xv) in relation to thiophene derivatives according to one of another preferred embodiment of the present invention are embodiments i) and iii) to x), wherein R ³ is hydroxy -C _{1 -5} - alkyl, 2,3- dihydroxy-propyl, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) 1- yl-methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2- [ (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine -3 - carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkyl} ester) 1-yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [( Pyrrolidin-3-carboxylic acid) -1-yl] -Ethyl, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3- [ (pi pyrrolidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone -2-carboxylic acid C _{1 -5-alkylester)} -1-yl] _{-propyl, -CH 2 - (CH 2)} n -COOH, -CH 2 - (CH 2) n -CONR 31 R 32, -CO —NHR ³¹ , or — (CH ₂ ) _n CH (OH) —CH ₂ —NR ³¹ R ³² and R ³¹ and R ³² are as defined in embodiment i) above.

xvi) in relation to thiophene derivatives according to any one of another preferred embodiment of the present invention are embodiments i) to x), wherein R ³ represents di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5} -alkoxy, 1-glyceryl, -OCH _2- (CH ₂ ) _m -NR ³¹ R ³² , -0-CH ₂ -CONR ³¹ R ³² , or -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ represents R ³² , wherein R ³¹ represents methyl or 2-hydroxyethyl and R ³² represents hydrogen.

xvii) Another very preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) to x), wherein R ³ is -CH _2- (CH ₂ ) _k -NHSO ₂ R ³³ , _{- (CH 2) n CH (} OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 -NHSO 2 R 33 , -CH _2- (CH ₂ ) _k -NHCOR ³⁴ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m -NHCOR ³⁴ , or -OCH ₂ -CH (OH) —CH ₂ —NHCOR ³⁴ , wherein R ³³ and R ³⁴ are as defined in embodiment i) above.

xviii) Another very preferred embodiment of the invention relates to the thiophene derivative according to any one of embodiments i) and iii) to x), wherein R ³ is -CH _2- (CH ₂ ) _n -COOH, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CH _2- (CH ₂ ) _k -NHSO ₂ R ³³ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NHSO ₂ R ³³ ,- _{OCH 2 - (CH 2) m} -NHSO 2 R 33, -OCH 2 -CH (OH) -CH 2 - NHSO 2 R 33, -CH 2 - (CH 2) k -NHCOR 34, - (CH 2) n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m -NHCOR ³⁴ , or -OCH ₂ -CH (OH) -CH ₂ -NHCOR ³⁴ , wherein R ³¹ , R ³² , R ³³ and R ³⁴ are as defined in embodiment i) above.

xix) Specific thiophene derivatives according to formula (I) are as follows:

4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[ 1,2,4] oxadiazol-3-yl] -phenol,

2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol,

1- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,

(2S) -3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene -4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

(2R) -3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene -4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

1-methoxy-3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] phen Talen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,

2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol,

3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1 -ol,

Dimethyl- (2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine,

Dimethyl- (2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine,

2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenol,

2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol,

1- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,

(2S) -3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

(2R) -3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol,

1- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -3-methoxy-propan-2-ol,

2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol,

3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol,

(2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -dimethyl-amine,

3- [3,5-dimethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole,

4- (2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -morpholine,

3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamine,

(3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -methyl-amine,

(3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -dimethyl-amine,

2- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamino) -ethanol,

3- [3,5-dimethyl-4- (3-pyrrolidin-1-yl-propoxy) -phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole,

(3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -propyl-amine,

2- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamino) -propane-1,3-diol,

N _1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -ethane-1,2-diamine,

1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-2-carboxylic acid,

1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-3-carboxylic acid,

2- [4- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia- Cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -piperazin-1-yl] -ethanol,

2-amino-2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-S-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol,

(3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl-isopropyl-amine,

(3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl)-(2-ethoxy-ethyl) -amine,

2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-5-yl] -phenol,

2- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -ethanol,

1- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propan-2-ol,

3- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol,

3- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol,

2- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxymethyl} -propane-1,3-diol, and

3- (3-trifluoromethyl-phenyl) -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazole.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments, for example in the form of pharmaceutical compositions for enteral, parenteral, or topical administration. They are for example parenterally in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, for example rectally in the form of suppositories, for example parenterally in the form of injection solutions or infusion solutions. Or, for example, locally in the form of ointments, creams or oils.

The preparation of the pharmaceutical composition comprises the combination of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described above, optionally in combination with other therapeutically useful substances, to produce a pharmaceutically acceptable, non-toxic inert Herbal dosage forms, together with solid or liquid carrier materials and, if necessary, conventional pharmaceutical adjuvants, may also be made in a manner familiar to those skilled in the art (eg, Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood , CO, USA, 2001; see Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science).

Pharmaceutical compositions comprising a compound of formula (I) are useful for the prevention and / or treatment of diseases or disorders associated with an activated immune system.

Such diseases or disorders include rejection of transplanted organs such as kidneys, liver, heart, lungs, interest, cornea, and skin; Graft-versus-host disease caused by stem cell transplantation; Inflammatory bowel disease such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and ulcerative colitis, thyroiditis such as psoriasis, psoriatic arthritis, Hashimoto's thyroiditis, uveitis; Atopic diseases such as rhinitis, autoimmune syndromes including dermatitis, dermatitis; asthma; Type I diabetes; Post-infection autoimmune diseases including rheumatic fever and post-infection glomerulonephritis; Solid cancer and metastasis of cancer.

Preferably, diseases or disorders which are prevented or treated using the compound of formula (I) include rejection of transplanted organs selected from kidney, liver, heart and lung; Graft-versus-host disease caused by stem cell transplantation; Autoimmune syndromes selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease, and Hashimoto's thyroiditis; And atopic dermatitis.

The invention also relates to a method of preventing or treating a disease or disorder referred to herein, comprising administering to a patient a pharmaceutically active amount of a compound of formula (I).

Moreover, the compounds of formula (I) are also useful when used in combination with one or several immunomodulators for the prophylaxis and / or treatment of the diseases and disorders mentioned herein. According to a preferred embodiment of the invention, the agents are selected from the group consisting of immunosuppressants, corticosteroids, NSAIDs, cytotoxic drugs, adhesion molecule inhibitors, cytokines, cytokine inhibitors, cytokine receptor antagonists and recombinant cytokine receptors. .

Yet another object of the present invention is a method of preparing a pharmaceutical composition comprising a compound of formula (I) by mixing one or more active ingredients with an inert excipient in a known manner.

The invention also provides the use of a compound of formula (I) in the preparation of a pharmaceutical composition for use in the prevention and / or treatment of the diseases and disorders mentioned herein, optionally in combination with one or several immunomodulatory agents. Related to

The invention also relates to prodrugs of compounds of formula (I) which convert in vivo to compounds of formula (I). It is therefore to be understood that reference to a compound of formula (I) also refers to the appropriate prodrug of the compound of formula (I) as appropriate and suitable.

Compounds of formula (I) can be prepared by the methods given below, by the methods given in the examples, or by analogous methods. Optimum reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

Compounds of formula (I) of the present invention may be prepared according to the general reaction chain outlined below. Only a few of the methods of synthesis resulting in compounds of formula (I) have been described.

Compounds of formula (I) wherein formula (I) is 5-thiophen-2-yl- [1,2,4] oxadiazole derivatives include acids (eg, TFA, acetic acid, HCl, etc.), bases (eg, NaH, NaOAc, Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, etc., tetraalkylammonium salts, or water scavengers (eg, oxalylchloride, carboxylic anhydride, POCl ₃ , PCl ₅ , P ₄ O ₁₀ , Reacting the compound of structure 1 in a solvent such as xylene, toluene, benzene, pyridine, DMF, dichloromethane, acetic acid, trifluoroacetic acid, etc., at room temperature or at elevated temperature, in the presence or absence of an adjuvant such as a molecular sieve, etc. (See, eg, ARGangloff, J. Litvak, EJ Shelton, D. Sperandio, VR Wang, K. Rice, Tetrahedron Lett. 42 (2001), 1441-1443; T. Suzuki, K. Iwaoka, N.). Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem. Pharm. Bull. 47 (1999), 120-122; RF Poulai, Tartar, BP Deprez, Tetrahedron Lett. 42 (2001), 1495-1498; RM Sriva stava, FJS Oliveira, DS Machado, RM Souto-Maior, Synthetic Commun. 29 (1999), 1437-1450; EO John, JM Shreeve, Inorganic Chemistry 27 (1988), 3100-3104; B. Kaboudin, K. Navaee, Heterocycles 60 (2003), 2287-2292).

The compound of structure 1 may be prepared in the presence or absence of one or more coupling agents such as TBTU, DCC, EDC, HBTU, HOBt, CDI, and the like, and in the presence of a base such as triethylamine, phoenix base, NaH, K ₂ CO ₃ , and the like, or It may also be prepared by reacting a compound of structure 2 with a compound of structure 3 in a solvent such as DMF, THF, etc. in the absence (see, eg, A. Hamze, J.-F. Hernandez, P. Fulcrand, J. Martinez, J. Org. Chem. 68 (2003) 7316-7321; and references cited above).

The compound of structure 3 is a compound of structure 4 in hydroxylamine or a salt thereof in a solvent such as methanol, ethanol, pyridine, etc., in the presence or absence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, and the like. It may also be prepared by reacting with one (see, eg, T. Suzuki, K. Iwaoka, N. Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem. Pharm. Bull). 47 (1999), 120-122; J. Cui, D. Crich, D. Wink, M. Lam, AL Rheingold, DA Case, WT Fu, Y. Zhou, M. Rao, AJ Olson, ME Johnson, Bioorg. Med. Chem. 1 1 (2003), 3379-3392; R. Miller, F. Lang, ZJ Song, D. Zewge, WO 2004/035538; B. Kaboudin, K. Navaee, Heterocycles 60 (2003), 2287. -2292).

Structure 4

Despite the nature of the functional groups present in structures 1, 3 or 4 and at residues R ¹ to R ⁴ in formula (I), these functional groups may require temporary protection. Suitable protecting groups are known to those skilled in the art and include, for example, benzyl or trialkylsilyl groups for protecting alcohols, ketals for protecting diols, and the like. Such protecting groups may be used according to standard methodologies (eg, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley New York, 1991; PJ Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the preferred residues R ¹ to R ⁴ , in particular R ^3, may also follow the cyclization reaction of the compounds of structure 1 by carrying out the above reaction chain using appropriate precursors of the compounds of structures 1, 3 and 4 respectively. May be introduced at the stage. Compounds of structure 4 or precursors thereof are prepared according to procedures commercially available or known to those skilled in the art.

Compounds of structure 2 may be selected from aq. NaOH, aq. LiOH, aq. Water-soluble bases such as KOH, and the like. Or aq. It may also be prepared by reacting an acid such as HC, TFA, etc. with a compound of structure 5.

Structure 5

The compound of structure 5 preferably uses a non-aqueous base such as NaOMe, NaOEt, KO-tert.-Bu, DBU, etc. in a solvent such as methanol, ethanol, THF, DMF, or the like at elevated temperature. It is prepared by treating the compound of structure 6.

       Structure 6 Structure 5

The compound of structure 6 is prepared by treating the compound of structure 7 with 2-mercaptoacetic acid ester in the presence of a base such as NaH in THF, dioxane, DMF, or mixtures thereof. The compounds of structure 2 may also be prepared in a single vessel three step reaction procedure starting from the compounds of structure 7 and following the reaction chain.

         Structure 7 Structure 6

When formula (I) represents 3-thiophen-2-yl- [1,2,4] oxadiazole derivatives, the compounds of formula (I) may be acid (eg, TFA, acetic acid, HCl, etc.), Bases (eg, NaH, NaOAc, Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, etc.), tetraalkyl ammonium salts, or water scavengers (eg, oxalyl chloride, carboxylic anhydride, POCl ₃ , PCl ₅ , P _1O O _4, molecular sieves, etc.), at room temperature or at an elevated temperature in the presence or absence of auxiliaries such as, xylene, toluene, benzene, pyridine, DMF, dichloromethane, in a solvent such as acetic acid, trifluoroacetic acid. It is prepared by reacting a compound of structure 8 (see, for example, the above).

Compounds of structure 8 may be prepared in the presence or absence of one or more coupling agents, such as EDC, HBTU, HOBt, CDI, and the like, in solvents such as DMF, THF, and the like, and triethylamine, Phoenix's base, NaH, K ₂ CO ₃ , etc., may be prepared by reacting a compound of structure 10 with a compound of structure 9 in the presence or absence of a base such as (see, eg, supra).

The compound of structure 9 may be substituted with the compound of structure 11 with hydroxylamine or a compound thereof in the presence or absence of a base such as Na ₂ CO ₃ , K ₂ CO ₃ , triethylamine, or the like in a solvent such as methanol, ethanol, pyridine, or the like. It can be prepared by reacting with one of the salts. (E.g., CD Bedford, RA Howd, OD Dailey, A. Miller, HW Nolen, RA Kenley, JR Kern, JS Winterle, J. Med. Chem. 29 (1986), 2174-2183, P. Dubus, B Decroix, J. Morel, P. Pastour, Annales de Chimie (Paris, France) 10 (1975) 331-336, and supra.

Structure 11

Despite the nature of the functional groups present in structures 8, 10 and the residues R ¹ to R ⁴ in formula (I), these functional groups may require temporary protection. Suitable protecting groups are known to those skilled in the art and include, for example, benzyl for protecting alcohols, or trialkylsilyl groups, ketals for protecting diols, and the like. Such protecting groups may be used according to standard methods (eg, TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley New York, 1991; PJ Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the necessary residues R ¹ to R ⁴ , in particular R ³ , in subsequent steps following the cyclization reaction of the compound of structure 8 by carrying out the reaction chain with the appropriate precursors of the compounds of structure 8 and 10, respectively May be introduced. Compounds of structure 10 or precursors thereof are prepared according to procedures commercially available or known to those skilled in the art.

The compound of structure 11 is prepared in a solvent such as ethanol, methanol, THF, dioxane, DMF or a mixture thereof. NaOH, aq. It may also be prepared by reacting a compound of structure 7 with a compound of structure 12 at a temperature of 20 to 100 ° C. in the presence of a base such as KOH, etc. (B. Hedegaard, JZ Mortensen, SO Lawesson, Tetrahedron 27 (1971), 3853 3859; and analogous to the preparation of the compound of structure 5 above).

Structure 7 Structure 12

(1S, 5R) -isomer of 2- [1-chloro-ethylidene] -6,6-dimethyl-bicyclo [3.1.0] hexane-3-one ((1S, 5R) -isomer of compound of structure 7 ) May be prepared starting from commercially available (+)-3- karen following the procedure given in the literature (eg SA Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and AV Tkachev, Tetrahedron Asymmetry 5 (1994), 479-489; SA Popov, AV Tkachev; Synthetic Commun. 31 (2001), 233-243).

The racemic form of structure 7 may be prepared starting from (+)-3-karen following the procedure given in the following literature, and is illustrated below (W. Cocker, DH Grayson, Tetrahedron Lett. 51 (1969), 4451-4452; S. Lochynski; B. Jarosz, M. Walkowicz, K. Piaktowski, J. Prakt. Chem. (Leipzig) 330 (1988), 284-288; M. Walkowicz, H. Kukyzynsky, C. Walkowicz, Roczniki Chemii Ann. Soc. Polm. Polonorum 41 (1967), 927-937; H. Kuczynski, M. Walkowicz, C. Walkowicz, K. Noowak, IZ Siemion, Roczniki Chemii Ann. Soc. Chim. Polonorum, 38 (1964), 1625-162 1633; AVPol, VGNaik, HRSonawane, Ind. J. Chem. Sect. B, 19 (1980) 603-604; SAPopov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and AVTkachev, Tetrahedron Asymmetry 5 (1994), 479-489; SAPopov, AVTkachev; Synthetic Commun. 31 (2001), 233-243).

 (1 R, 5S) -isomer of 2- [1chloro-ethylidene] -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one ((1R, 5S) -isomer of compound of structure 7 Compounds of formula (I) based on) may be incorporated into the pure enantiomer by racemic mixtures of compounds of formula (I), or one of their precursors, in a manner known to those skilled in the art, preferably by chromatography or crystallization. It may be obtained by dissolution.

Example

 The following examples illustrate the invention and do not at all limit the scope of the invention.

All temperatures are referred to as degrees Celsius. Compounds are either ¹ H-NMR (300 MHz) or ¹³ C-NMR (75 MHz) (Varian Oxford; chemical shifts are given in ppm relative to the solvent used; multiplicity: s = singlet, d = doublet, t = Triplet: p = quintet, hex = hex = hept = sevent, m = multiple, br = wide, coupling constant in Hz); by LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: 4.6x50 mm, Zorbax SB-AQ, 5 μιη, 120 μs, gradient: aceto in water with 0.04% trifluoroacetic acid Nitrile 5-95%, 1 min, flow rate: 4.5 mL / min), tR is given in minutes; TLC (TLC-plate from Merck, Silica Gel 60 F254); Or by melting point. Compounds were preparative HPLC (column: X-terra RP18, 50x19 mm, 5 μιη, gradient: acetonitrile 10-95% in water containing 0.5% formic acid) or MPLC (Labomatic MD-80-100 pump, linear UVIS-201 detector, column: 350x18 mm, Labogel-RP-18-5s-100, gradient: 10% methanol to 100% methanol in water).

Abbreviations (as used herein)

approx. about

aq. Mercury

atm air pressure

BSA Bovine Serum Albumin

Bu butyl

CC column chromatography

CDI Carbonyl Diimidazole

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DCC dicyclohexyl carbodiimide

DCM dichloromethane

DEAD diethylazodicarboxylate

DIPEA diisopropyl-ethylamine, phoenix base, ethyl-diisopropylamine

DMF Dimethylformamide

DMSO dimethyl sulfoxide

DPPP 1,3-bis- (diphenylphosphino) -propane

EA ethyl acetate

EDC N- (3-dimethylaminopropyl) -N'-ethyl-carbodiimide

Et ethyl

h hours

HBTU O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethylruronium hexafluorophosphate

HOBt 1-hydroxybenzotriazole

HPLC high performance liquid chromatography

LC-MS Liquid Chromatography- Mass Spectrometer

Me methyl

min min

MPLC Medium Pressure Liquid Chromatography

OAc Acetate

prep. Spare

TBTU 2- (1H-benzotriazol-1-yl) -1,2,3,3-tetramethylruronium tetrafluoroborate

TFA trifluoroacetic acid

THF tetrahydrofuran

rt room temperature

sat. Saturated

S1P sphingosine 1-phosphate

TLC thin layer chromatography

tR dwell time

(1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid ethyl ester (compound of structure 5)

a) NaH (7.0 g, 60% dispersion in mineral oil, 175 mmol) is rinsed with pentane (100 mL) and suspended in THF (400 mL). The suspension is cooled to 0 ° C. and a solution of ethyl 2-mercaptoacetate (12.62 g, 105 mmol) in THF (50 mL) is added over 20 min. The temperature of the reaction is maintained at 5-10 ° C. Upon completion of addition, cooling is removed and stirring is continued for 30 min. Solution of (1S, 5R) -2- (1-chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (SA in THF (50 mL) (SA Popov, A. Yu. Denisov, Yu. V. Gatilov, I. Yu. Bagryanskaya and AVTkachev, Tetrahedron Asymmetry 5 (1994), 479-489; SAPopov, AVTkachev; Synthetic Commun. 31 (2001), 233-243) ( 12.93 g, 70 mmol) is added to the suspension and the resulting mixture is stirred at rt for 1.5 h. The mixture is filtered, the filtrate is concentrated to about 100 ml, 1 M aq. Dilute with NaOH (100 ml) and extract twice with DCM (150 ml). The extract was dried over Na ₂ S0 ₄ and evaporated to {1-[(1S, 5R) -6,6-dimethyl-3-oxo-bicyclo [3.1.0] hexylidene] -ethylsulfanyl} A crude E / Z mixture of acetic acid ethyl ester (18.2 g) is provided as a brown oil. LC-MS: t _R 1.00 min, [M + 1] < + > = 269.13. ¹ H NMR (CDCl ₃ ): δ 4.22 (q, J = 7.0 Hz, 2H all isomers), 3.67 (d, J = 15.8 Hz, 1H multiple isomers), 3.63 (d, J = 15.8 Hz, 1H minor isomers) , 3.58 (d, J = 15.8 Hz, 1H polyisomer), 3.54 (d, J = 15.8 Hz, 1H, minor isomer), 2.67 (dd, J = 6.4, 19.4 Hz, 1H minor isomer), 2.60 (dd, J = 7.0, 19.4 Hz, 1H polyisomer), 2.58 (s, 3H minor isomers), 2.52 (s, 3H polyisomers), 2.36-2.32 (m, 1H polyisomers), 2.30-2.26 (m, 1H polyisomers) , 1H minority isomer), 2.18 (d, J = 7.0 Hz, 1H minority isomer), 2.00 (d, J = 7.0 Hz, 1H majority isomer), 1.95 (d, J = 7.6 Hz, 1H minority isomer), 1.30 ( t, J = 7.0 Hz, 3H majority isomer), 1.28 (t, J = 7.0 Hz, 3H minor isomer), 1.18 (s, 3H majority isomer), 1.15 (s, 3H minor isomers), 0.89 (s, 3H minor isomers) Isomers), 0.85 (s, 3H multiple isomers).

b) abs. A solution of Na (1.70 g, 74.8 mmol) in ethanol (75 ml) was heated to 60 ° C. and then abs. Crude {1-[(1S, 5R) -6,6-dimethyl-3-oxo-bicyclo [3.1.0] hex- (2Z) -ylidene] -ethylsulfanyl} in ethanol (200 ml) Treated with a solution of acetic acid ethyl ester (18.2 g, 68.0 mmol). The mixture was stirred at 75 ° C. for 20 min, then cooled to rt and 0.5 M aq. Dilute with NaOH (500 ml) and extract with DCM (450 + 200 ml). The combined extracts are dried over Na ₂ S0 ₄ , filtered and the solvent is removed in vacuo. It is crude (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid ethyl ester (10.5 g) Is provided as a yellow oil of 87% purity (LC-MS, UV 280 nm). LC-MS: t _R = 1.11 min, [M + 1] < + > = 251.14; ¹ H NMR (CDCl ₃ ): δ 4.26 (q, J = 7.0 Hz, 2H), 2.95 (dp, Jd = 18.8 Hz, Jp = 3.5 Hz, 1H), 2.79 (d, J = 19.3, 1H), 2.37 (s, 3H), 1.89-1.84 (m, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.12 (s, 3H), 0.72 (s, 3H).

(1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid (compound of structure 2)

Crude (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid in ethanol (200 ml) To a solution of ethyl ester (10.3 g, 41.2 mmol), 2N aq. A solution of LiOH (300 ml) is added. The resulting mixture is stirred for 1 h at 70 ° C., cooled to rt and diluted with water (250 ml). The aq. Solution is extracted three times with DCM (125 ml) and then acidified to pH 3 by addition of citric acid. The acidified solution is extracted twice using DCM (2x250 ml). This second extract is combined, dried over Na ₂ SO ₄ , filtered and evaporated to give (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia -Cyclopropa [a] pentane-4-carboxylic acid (7.0 g) is left as a yellow solid. LC-MS: t _R = 0.95 min, [M + 1] < + > = 223.00. ¹ H NMR (CDCl ₃ ): δ 3.04-2.92 (m, 1H), 2.83 (d, J = 19.3 Hz, 1H), 2.39 (s, 3H), 1.91-1.87 (m, 2H), 1.13 (s, 3H), 0.73 (s, 3H).

Alternatively, (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid may be added to the following procedure Obtained accordingly: To a solution of sodium in ethanol (400 mL) (2.80 g, 122 mmol) is added a solution of mercapto-acetic acid ethyl ester (14.64 g, 122 mmol) in ethanol (40 mL). The solution was stirred for 5 min and then (1S, 5R) -2- (1-chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3.1.0] hexane in ethanol (40 mL) 3-one (15.0 g, 81.2 mmol) is added dropwise. The solution is slightly warmed (approx. 30 ° C.) and changes from orange to brown. Fine precipitates are formed. Stirring is continued at rt for 1 h. Then a solution of sodium (2.24 g, 97.5 mmol) in ethanol (75 mL) is added quickly and the mixture is heated to 75 ° C. for 1 H. A 2N aqueous solution of LiOH (75 mL) was added and stirring continued at 75 ° C. for 2 h, followed by stirring at rt for 16 h. About 2/3 of the solvent is removed in vacuo and the remaining mixture is diluted with water (250 mL) and extracted using DCM (200 mL). The organic extract was 1 N aq. Rinse twice with (100 mL). The combined aqueous layer was 2N aq. Acidified by addition of HCl and extracted three times with diethyl ether (3x300 ml). The organic extract is dried over MgSO ₄ and evaporated. The remaining residue is suspended in acetonitrile, filtered, rinsed with additional acetonitrile and dried under high vacuum to give the title compound (12.02 g) as a pale yellow to beige crystalline powder.

rac- (1S, 5R) -2- [1-chloro-S- (E) -ylidene] -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (compound of structure 7)

a) N-bromo-succinate is added to a suspension of (+)-3-karen (82 g, 0.6 mol) and CaCO3 (80 g, 0.8 mol) in water (300 ml) and dioxane (600 ml) Mid (142 g, 0.8 mol) is added. The mixture is stirred at rt for 1 H, diluted with water (1500 ml) and extracted with diethyl ether (500 ml). The organic extract was water (3x1000 ml) and 5% aq. Rinse with Na2S2O3 (2x500 ml) and dry over Na ₂ S0 ₄ . The solvent is removed under reduced pressure and the crude product is purified by column chromatography on silica gel eluting with 4: 1 hexanes / EA to give (1S, 3R, 4R, 6R) -4--bromo -3,7,7-trimethyl-bicyclo [4.1.0] heptan-3-ol (48.3 g) is calculated as a beige solid. ¹ H NMR (CDCl ₃ ): δ 4.05 (dd, J = 7.6, 10.6 Hz, 1H), 2.48-2.36 (m, 2H), 2.20 (dd, J = 10.0, 14.7 Hz, 1H), 1.42-1.38 ( m, 1H), 1.36 (s, 3H), 1.02 (s, 3H), 0.98 (s, 3H), 0.90-0.80 (m, 1H), 0.72-0.66 (m, 1H).

b) (1S, 3R, 4R, 6R) -4-bromo-3,7,7-trimethyl-bicyclo [4.1.0] heptan-3- in water (120 ml) and dioxane (1600 ml) Ag ₂ O (156.4 g, 0.675 mol) is added to a solution of all (58.0 g, 0.25 mol). The resulting suspension is stirred at rt for 18 h and then filtered through celite. The filtrate is evaporated under reduced pressure. The remaining solid is dissolved in diethyl ether (650 ml) and rinsed with water (2x 1000 ml). The organic extract was dried over Na ₂ SO ₄ and the solvent was removed in vacuo to give 1-((1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hex-3-yl) -ethane On (36.6 g) is provided as a pale yellow oil. ¹ H NMR (CDCl ₃ : δ 2.83-2.70 (m, 1H), 2.14-2.03 (m, 5H), 1.82 (dd, J = 10.0, 14.1 Hz, 2H), 1.16-1.13 (m, 2H), 0.95 (s, 6H).

c) of 1-((1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hex-3-yl) -ethanone (36.5 g, 0.24 mol) in DCM (700 ml) To the solution is partially added 70% m-chloroperbenzoic acid (77 g, 0.312 mol). The reaction mixture was stirred at rt for 36 h and then 0.2 N aq. Rinse with NaOH (1000 ml). Rinse solution is extracted again with DCM (2x300 ml). The combined organic extracts were dried over MgSO ₄ and the solvent removed in vacuo to give acetic acid (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hex-3-yl ester (37.8 g ) As a pale yellow oil. ¹ H NMR (CDCl ₃ ): δ 4.94 (hept. J = 3.5 Hz, 1H), 2.02-1.93 (m, 5H), 1.87-1.78 (m, 2H), 1.22-1.15 (m, 2H), 0.95 ( s, 3H), 0.83 (s, 3H).

d) A solution of acetic acid (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hex-3-yl ester (37.85 g, 225 mmol) in ethanol (700 ml) gave 2 N aq . Treated with LiOH (700 ml). The mixture is stirred at rt for 1 H, diluted with water (600 ml) and extracted using EA (2 × 150 ml). The combined organic extracts were dried over MgSO ₄ and evaporated to give (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-ol (23.9 g) as pale yellow oil. to provide. ¹ H NMR (CDCl ₃ ): δ 4.23 (hept, J = 2.9 Hz, 1H), 1.87-1.70 (m, 4H), 1.23-1.20 (m, 2H), 0.96 (s, 3H), 0.81 (s, 3H).

e) CrO3 (50 g, 0.5 mol) is added to a mixture of pyridine (80 ml) and DCM (720 ml). The mixture is stirred for 5 min and then (1S, 3S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-ol (11.5 g, 0.08 mol) is added. Agitation is continued for 2.5 h at rt. The mixture is decanted from the oily residue, diluted with DCM (100 ml) and 2N aq. After rinsing with HCl (3 × 80 ml), sat. aq. Rinse with NaHCO ₃ solution (80 ml). The separated organic phase is dried over NaSO 4 and the solvent is removed in vacuo to give (1S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one as a pale yellow oil. ¹ H NMR (CDCl ₃ ): δ 2.58-2.46 (m, 2H), 2.19-2.1 1 (m, 2H), 1.34-1.26 (m, 2H), 1.09 (s, 3H), 0.87 (s, 3H) .

f) Methyl acetate (2.22 g, 30 mmol) is added to a suspension of NaH (873 mg, 55% dispersion in mineral oil, 20 mmol, rinsed with dioxane before use) in dioxane (15 ml). The suspension is stirred at rt for 5 min and of (1S, 5R) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (1.24 g, 10 mmol) in dioxane (5 ml). Solution is added. The reaction mixture is stirred at 65 ° C. overnight. The mixture was cooled to 10% aq. Pour into citric acid solution (75 ml) and extract with DCM (3x75 ml). The organic extract is rinsed with water, dried over MgSO ₄ and evaporated to afford crude racemic (1R, 2R, 5R) -2-acetyl-6,6-dimethyl-bicyclo [3.1.0] hexan-3-one. (2.45 g, containing dioxane) is provided as a dark yellow liquid. ¹ H NMR (CDCl ₃ ): δ 2.61 (dd, J = 7.3, 19.6 Hz, 1H), 2.34-2.20 (m, 1H), 2.01 (s, 3H), 1.72 (d, J = 8.2 HZ, 1H) , 1.40-1.20 (m, 2H), 1.09 (s, 3H), 0.81 (s, 3H).

g) A mixture of said yellow liquid (1.66 g, 10 mmol), triphenylphosphine (4.53 g, 17 mmol) and CCI4 (5 ml) in chloroform (15 ml) is heated to 65 ° C. for 1 h. The mixture is concentrated and the remaining residue is stirred with pentane. The pentane is decanted out and the remaining residue is treated once more using pentane. Pentane fractions were combined and concentrated to give rac- (1S, 5R) -2- [1-chloro-S- (E) -ylidene] -6,6-dimethyl-bicyclo [3.1.0] hexane-3- Warm (1.9 g) is left as brown oil. This material is used in the next step without further purification. LC-MS: t _R = 0.12 min.

(1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop-pa [a] pentalene-4-carbonitrile (compound of structure 11)

(1S, 5R) -2- (1-Chloro- (E) -ethylidene) -6,6-dimethyl-bicyclo [3.1.0] hexan-3-one (997 mg, in THF (37 ml) 5.40 mmol) and thioacetic acid S-cyanomethyl ester (746 mg, 6.48 mmol) gave 2 N aq. Treated with NaOH (10.8 ml). The resulting mixture is vigorously stirred at rt for 2 h. Thioacetic acid S-cyanomethyl ester (100 mg, 0.87 mmol) and 2 N aq. Another portion of NaOH (2 ml) is added and stirring is continued for 1 h. The reaction mixture is 2 N aq. Dilute with NaOH and extract twice with DCM. The organic extract is dried over Na ₂ S0 ₄ and evaporated. The remaining brown oil is dissolved in THF (30 ml) and 2 N aq. Treated with NaOH (3 ml). The mixture was heated to 90 ° C. for 4 h and then 2 N aq. Dilute with NaOH and extract with DCM. The organic extract is dried over Na ₂ S0 ₄ and evaporated. The crude product was prep. Purified by HPLC (Phenomenex Aqua 30x75 mm, 10-95% acetonitrile slope in water containing 0.5% formic acid), (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5, 5a-tetrahydro-3-thia-cyclopro-pa [a] pentane-4-carbonitrile (650 mg) is provided as a brown oil; LC-MS: t _R = 1.06 min, [M + 1 + CH 3 CN] + = 245.1 1; ¹ H NMR (CDCl ₃ ): 5 2.90 (dd, J = 5.9, 18.8 Hz, 1H), 2.68 (d, J = 18.8 Hz, 1H), 2.38 (s, 3H), 1.96-1.88 (m, 2H) , 1.13 (s, 3 H), 0.72 (s, 3 H).

(1aS, 5aR) -N-hydroxy-1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxamidine ( Compound of structure 9)

To a stirred suspension of K-tert.-butylate (281 mg, 2.5 mmol) and hydroxylamine hydrochloride (208 mg, 3.0 mmol) in methanol (4 ml) (1aS, 5aR) -1,1,2 Trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopro-pa [a] pentalene-4-carbonitrile (203 mg, 1.0 mmol) is added. The reaction mixture is stirred at rt for 5 h and then filtered. The filtrate was prep. Purified by HPLC (Water XTerrra Prep MS C18 30x75 mm, 10% to 95% acetonitrile in water containing 0.5% sat. Aq. NH3), (1aS, 5aR) -N-hydroxy-1, 1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxamidine (200 mg) is provided as a colorless solid; LC-MS: t _R = 0.72 min, [M + 1] + 237.09.

Methanesulphonic acid 2,2-dimethyl- [1,3] dioxan-5-ylmethyl ester

Title compounds include B. Xu, A. Stephens, G. Kirschenheuter, A. F. Greslin, X. Cheng, J. Sennelo, M. Cattaneo, M. L. Zighetti, A. Chen, S.-A. Kim, H. S. Kim, N. Bischofberger, G. Cook, K. A. Jacobson, J. Med. Chem. 45 (2002) 5694-5709.

Example 1

a) of 2,4-dimethoxybenzonitrile (3.25 g, 20 mmol), hydroxylamine hydrochloride (2.92 g, 42 mmol) and K ₂ CO ₃ (5.80 g, 42 mmol) in ethanol (80 ml) The mixture is stirred at 85 ° C. for 27 h and then poured into water (250 ml). The solution was 1 N aq. Acidified by addition of HCl (75 ml) and extracted once with DCM (100 ml). The aqueous layer was 1 N aq. Basified with NaOH (90 ml) and extracted three times with DCM (3 × 150 ml). The organic extract is dried over MgSO ₄ , the solvent is evaporated and the residue is dried under high vacuum to give N-hydroxy-2,4-dimethoxy-benzamidine (1.35 g) as a beige solid. LC-MS: t _R = 0.68 min, [M + 1] < + > = 197.11.

b) N-hydroxy-2,4-dimethoxy-benzamidine (98 mg, 0.50 mmol) in DMF (4 ml), (1aS, 5aR) -1,1,2-trimethyl-1,1a, A mixture of 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid (111 mg, 0.50 mmol), TBTU (178 mg, 0.55 mmol) and DIPEA (646 mg, 5 mmol) Is stirred at rt for 45 min and then at 110 ° C. for 1 h. The reaction mixture is immediately prep. HPLC purification (Phenomenex Aqua 75x30 mm, gradient with acetonitrile / water containing 0.5% formic acid) followed by 3- (2,4-dimethoxy-phenyl) -5-((1aS, 5aR) -1,1, Colorless 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole (19 mg) Served as lyophilisate; LC-MS: t _R = 1.17 min, [M + I] < + > = 383.13; ¹ H NMR (CDCl ₃ ): δ 7.89 (d, J = 8.8 Hz, 1H), 6.46 (dd, J = 2.3, 8.8 Hz, 1H), 6.43 (d, J = 2.3 Hz, 1H), 3.83 (s , 3H), 3.74 (s, 3H), 2.96 (dd, J = 5.9, 18.8 Hz, 1H), 2.80 (d, J = 18.8 Hz, 1H), 2.29 (s, 3H), 1.88-1.78 (m, 2H), 1.02 (s, 3H), 0.63 (s, 3H).

Example 2

a) K-tert.-butylate (28.28 g, 252 mmol) and then hydroxylamine hydrochloride (15.0 g, 216 mmol) are carefully added to dry methanol (285 mL). The suspension is stirred for 30 min and then 4-hydroxybenzonitrile (8.58 g, 72 mmol) is added. The mixture is refluxed for 40 h, the solvent is evaporated and the residue is 2 N aq. Acidified by addition of HCl. The solution is extracted twice with DCM (100 mL). The aqueous layer is aq. It is basified by adding solid NaHCO ₃ . The resulting precipitate was filtered, rinsed with water and dried to give 4, N-dihydroxy-benzamidine (7.6 g) as a brown solid; ¹ H NMR (D ₆ -DMSO): δ 9.57 (s, 1H), 9.33 (s, 1H), 7.48-7.42 (m, 2H), 6.74-6.68 (m, 2H), 5.62 (s, 2H).

b) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid in DMF (35 mL) (3.50 g, 15.74 mmol), TBTU (5.56 g, 17.32 mmol) and a solution of DIPEA (8.89 mL, 51.96 mmol) were stirred at rt for 10 min before 4, N-dihydroxy-benzamidine (2.64 g , 17.32 mmol) is added. The solution is stirred for further 30 min, formic acid is added (7 mL) and the solution is prep. Chromatographed by HPLC (Grom-Sil 120 ODS-4-HE, 30x75 mm, gradient with acetonitrile / water containing 0.5% formic acid), (1aS, 5aR) -1,1,2-trimethyl-1 , 1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid N- (4-hydroxy- (hydroxybenzamidine)) ester (4.5 g) as colorless solid Provided as; LC-MS: t _R = 0.97 min, [M + 1] < + > = 357.14.

c) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid in toluene (450 mL) After a suspension of N- (N-hydroxy-4-hydroxy-benzamidine) ester (4.5 g, 12.63 mmol) is stirred at 105 ° C. for 48 h, the solvent is removed under reduced pressure. The residue is dissolved in acetonitrile / methanol and prep. Purified by HPLC (Grom-Sil 120 ODS-4-HE, 30 × 75 mm, gradient with acetonitrile / water containing 0.5% formic acid) to afford 4- [5-((1aS, 5aR) -1,1, 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenol (2.9 g) as a colorless solid; LC-MS: t _R = 1.11 min, [M + 1] < + > = 339.13; ¹ H NMR (CDCl ₃ ): δ 8.04-7.98 (m, 2H), 6.94-6.89 (m, 2H), 5.37 (s br, 1H), 3.10 (dd, J = 5.7, 18.8 Hz, 1H), 2.93 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.00-1.92 (m, 2H), 1.14 (s, 3H), 0.75 (s, 3H).

Examples 3-12

4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene in isopropanol (1 mL) To a solution of -4-yl)-[1,2,4] oxadiazol-3-yl] -phenol (10 mg, 0.03 mmol) with the corresponding alkylating agent (as bromine, chlorine or mesylate) (0.15 mmol) and 2 N aq. NaOH (0.2 mL) is added. The reaction mixture is mixed at 70 ° C. for 8 h. The reaction mixture was prep. Purified by HPLC (Waters XTerra Prep MS C18 19x50mm 5μm, 90% to 5% water (0.8% NEt2) / acetonitrile or Waters Symmetry C18 19x50mm 5um, 90% to 5% water (0.5% HCOOH) / acetonitrile) The desired product is provided as a colorless lyophilisate. In the case of Example 8 the reaction mixture is stirred at 85 ° C. for 8 h and then TFA (0.3 ml) is added. The mixture is prep. Mix for another hour at 60 ° C. prior to purification by HPLC.

Example 13

a) K-tert.-butylate (18.68 g, 166 mmol) and then hydroxylamine hydrochloride (9.92 g, 143 mmol) are carefully added to dry methanol (190 ml). The suspension is stirred for 30 min and then 3,5-dimethyl-4-hydroxybenzonitrile (7.00 g, 147 mmol) is added. After the mixture was refluxed for 32 h, the suspension was quenched with 2 N aq. Dilute by adding HCl. The solution is extracted twice using DCM (100 ml). The aqueous layer is basified by adding solid NaHCO ₃ (pH 9), extracted five times with DCM and then four times with EA. The combined organic layers were dried over Na ₂ SO ₄ and evaporated to dryness to give 4, N-dihydroxy-3,5-dimethyl-benzamidine (7.9 g) as a colorless solid; LC-MS: t _R = 0.62 min, [M + 1] < + > = 181.14.

b) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid in DMF (30 ml) (3.00 g, 13.50 mmol), TBTU (4.77 g, 14.85 mmol) and a solution of DIPEA (7.62 ml, 44.53 mmol) were stirred at rt for 10 min before 4, N-dihydroxy-3,5-dimethyl- Benzamidine (2.68 g, 14.85 mmol) is added. The solution is further stirred for 20 min, formic acid (6 ml) is added and the solution is prep. Chromatographed by HPLC (Grom-Sil 120 ODS-4-HE, 30x75 mm, gradient with acetonitrile / water containing 0.5% formic acid), (1aS, 5aR) -1,1,2-trimethyl-1 , 1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid N- (3,5-dimethyl-4-hydroxy-N-hydroxybenzamidine) ester ( 4.1 g) is provided as a colorless solid; LC-MS: t _R = 1.03 min, [M + 1] < + > = 385.18; ¹ H NMR (D ₆ -DMSO): δ 8.65 (s, 1H), 7.30 (s, 2H), 6.38 (s br, 2H), 3.04 (dd, J = 5.9, 18.8 Hz, 1H), 2.75 (d , J = 18.8 Hz, 1H), 2.36 (s, 3H), 2.18 (s, 6H), 2.01 -1.88 (m, 2H), 1.10 (s, 3H), 0.70 (s, 3H).

c) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid in toluene (400 mL) A suspension of N- (3,5-dimethyl-4-hydroxy-N-hydroxybenzamidine) ester (4.0 g, 10.41 mmol) is stirred at 100 ° C. for 24 h before the solvent is removed under reduced pressure. The residue was purified by column chromatography on silica gel dissolved in DCM and eluting with 5: 1 hexanes: EA to give 2,6-dimethyl-4- [5-((1aS, 5aR) -1 , 1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl ] -Phenol (1.5 g) is provided as a colorless solid; LC-MS: t _R = 1.37 min, [M + 1] < + > = 367.13; ¹ H NMR (CDCl ₃ ): δ 7.75 (s, 2H), 4.90 (s, 1H), 3.12 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H), 2.44 (s, 3H), 2.32 (s, 6H), 2.02-1.94 (m, 2H), 1.16 (s, 3H), 0.77 (s, 3H).

Examples 14-18 and 20-23

2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop in isopropanol (1 ml) Corresponding alkylating agents (as bromine, chlorine or mesylate) to a solution of pa [a] pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenol (10 mg, 0.027 mmol) (0.135 mmol) and 2 N aq. NaOH (0.2 ml) is added. The reaction mixture is mixed at 65 ° C for 10 h. The reaction mixture was prep. Purification by HPLC (Waters XTerra Prep MS C18 19 × 50 mm 5 um, 80% to 5% water (0.85% NEt 2) / acetonitrile) gives the desired product as a colorless lyophilisate.

Example 14

¹ H NMR (CDCl ₃ ): δ 7.78 (s, 2H), 4.00-3.90 (m, 4H), 3.12 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H) , 2.43 (s, 3H), 2.36 (s, 6H), 2.14 (t br, J = 5 Hz, 1H), 2.01-1.92 (m, 2H), 1.15 (s, 3H), 0.76 (s, 3H) .

Example 16

¹ H NMR (CDCl ₃ ): δ 7.78 (s, 2H), 4.17-4.08 (m, 1H), 3.94-3.80 (m, 4H), 3.11 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 ( d, J = 18.8 Hz, 1H), 2.72 (d br, J = 3.5 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 6H), 2.06 (s br, 1H), 2.01 -1.90 (m , 2H), 1.14 (s, 3H), 0.76 (s, 3H).

Example 20

¹ H NMR (CDCl ₃ ): δ 7.78 (s, 2H), 4.01 -3.92 (m, 4H), 3.11 (dd, J = 5.9, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H) , 2.43 (s, 3H), 2.35 (s, 6H), 2.14-2.03 (m, 2H), 2.00-1.91 (m, 3H), 1.15 (s, 3H), 0.76 (s, 3H).

Example 19

a) DEAD (0.097 ml, 0.615 mmol) is added to a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF. The solution was stirred at rt for 1 h, then (2,2-dimethyl- [1,3] dioxan-5-yl) -methanol (90 mg, 0.615 mmol) and 2,6-dimethyl-4- [5- ((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl)-[1,2,4 ] Oxadiazol-3-yl] -phenol (150 mg, 0.410 mmol) is added. Stirring is continued for 24 h. The reaction mixture was prep. Purified by HPLC (Waters XTerra Prep MS C18 19 × 50 mm 5 μm, water (0.85% NEt 2) / acetonitrile), 3- [4- (2,2-dimethyl- [1,3] dioxan-5-ylmethoxy ) -3,5-dimethyl-phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] phen Talen-4-yl)-[1,2,4] oxadiazole (135 mg) is provided as a colorless lyophilisate; LC-MS: t _R = 1.29 min, [M + 1] < + > = 495.30.

b) 3- [4- (2,2-dimethyl- [1,3] dioxan-5-ylmethoxy) -3,5 in 4: 1 acetic acid / water (4 mL) and THF (2 mL) -Dimethyl-phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl A suspension of)-[1,2,4] oxadiazole (135 mg, 0.273 mmol) is stirred at rt for 3 h. Then, approx. In isopropanol (1 mL). 6 N HCl is added and stirring is continued for 30 min. Diethylamine (0.2 mL) is added to the mixture, after which prep. Purified by HPLC (Grom-Sil 120 ODS-4-HE, 30x75 mm, 10 um, acetonitrile / water (0.5% HCOOH), 20% to 95% acetonitrile) to afford 2- {2,6-dimethyl- 4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[ 1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol (50 mg) as a colorless resin; LC-MS: t _R = 1.12 min, [M + 1] < + > = 455.22; ¹ H NMR (CDCl ₃ ): δ 7.78 (s, 2H), 4.05-4.00 (m, 4H), 3.98-3.94 (m, 2H), 3.1 1 (dd, J = 6.4, 18.8 Hz, 1H), 2.94 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.35 (s, 6H), 2.32-2.23 (m, 1H), 2.14 (s br, 2H), 2.00-1.92 (m, 2H) , 1.15 (s, 3 H), 0.76 (s, 3 H).

Examples 24-34, 36, and 37

a) isopropanol (6.8 ml) and 2 N aq. 2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop in NaOH (2.3 ml) 3-bromoethanol (0.12 ml, 1.42 mmol) in a solution of pa [a] pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenol (250 mg, 0.68 mmol) ) Is added. The reaction mixture is stirred at 65 ° C for 13 h. The solution was 0.5 N aq. Poured with HCl and extracted twice with DCM. The organic extract is dried over MgSO ₄ and evaporated. The crude product was purified by column chromatography on silica gel eluting with 22: 1 DCM: TBME to afford 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1 , 1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl ] -Phenoxy} -propan-1-ol (170 mg, Example 20) is provided as a beige resin; LC-MS: t _R = 1.20 min, [M + 1] < + > = 425.20.

b) 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a in DCM (5 ml) at 0 ° C. -Tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol (170 mg , 0.40 mmol) and DIPEA (0.1 1 ml, 0.64 mmol) are treated with methanesulfonyl chloride (0.04 ml, 0.48 mmol). The reaction mixture was stirred at 0 ° C. for 30 min, then at rt for 1 h and then diluted with DCM (15 ml) and 0.1 N aq. After rinsing with NaOH (20 ml), 10% aq. Rinsed with citric acid solution (20 ml). The organic layer was dried over Na ₂ S0 ₄ and evaporated to dryness to allow methanesulphonic acid 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl -1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy}- Propyl ester (185 mg) is provided as a beige resin; LC-MS: t _R = 1.23 min, [M + 1] < + > = 503.20.

c) methanesulphonic acid 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3 in DMF -Thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl ester (9 mg, 0.017 mmol), corresponding amine (0.067 mmol) and DIPEA (0.025 ml) are mixed at 85 ° C. for 7 h. The reaction mixture is prep. Purification by HPLC (Waters Xterra MS18 19 × 50 mm 5 um, 90% to 5% 0.1 N aq. HCl / acetonitrile) gives the desired product as a colorless lyophilisate.

Example 27 (as hydrochloride)

¹ H NMR (D ₆ -DMSO): δ 8.81 (s br, 2H), 7.67 (s, 2H), 5.25 (t br, J = 5 Hz, 1H), 3.88 (t, J = 5.9 Hz, 2H) , 3.71 -3.64 (m, 2H), 3.20-3.00 (m, 5H), 2.84 (d, J = 18.8 Hz, 1H), 2.41 (s, 3H), 2.30 (s, 6H), 2.18-1.96 (m , 4H), 1.10 (s, 3H), 0.70 (s, 3H).

Example 35

a) DEAD (0.097 ml, 0.615 mmol) is added to a solution of triphenylphosphine (161 mg, 0.615 mmol) in dry THF (2.5 ml). The solution was stirred at rt for 1 h, then (2,2-dimethyl-5-nitro- [1,3] dioxan-5-yl) -methanol (1 18 mg, 0.615 mmol) and 2,6-dimethyl- 4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop-pa [a] pentalen-4-yl)- [1,2,4] oxadiazol-3-yl] -phenol (150 mg, 0.410 mmol) is added. Agitation is continued for 7 days. The precipitate formed is collected, rinsed with isopropanol and dried under high vacuum to give 3- [4- (2,2-dimethyl-5-nitro- [1,3] dioxan-5-ylmethoxy) -3,5-dimethyl- Phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl)-[ 1,2,4] oxadiazole (90 mg) as an almost colorless solid; LC-MS: t _R = 1.30 min, [M + 1] < + > = 540.28; ¹ H NMR (CDCl ₃ ): δ 7.77 (s, 2H), 4.50 (d, J = 12.9 Hz, 2H), 4.29-4.21 (m, 4H), 3.10 (dd, J = 6.4, 18.8 Hz, 1H) , 2.93 (d, J = 18.8 Hz, 1H), 2.43 (s, 3H), 2.28 (s, 6H), 2.00-1.91 (m, 2H), 1.48 (s, 3H), 1.45 (s, 3H), 1.15 (s, 3 H), 0.76 (s, 3 H).

b) 3- [4- (2,2-dimethyl-5-nitro- [1,3] dioxan-5-ylmethoxy) -3 in 20: 4: 1 THF: TFA: water (12.5 ml) , 5-dimethyl-phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4 -Yl)-[1,2,4] oxadiazole (85 mg, 0.158 mmol) is stirred at 65 ° C. for 4.5 h. The mixture is further diluted with 2: 1 TFA: water and stirring is continued at 65 ° C. for 3 h. The mixture is cooled to rt and 2N aq. Poured into NaOH and extracted twice with DCM. The organic extract was dried over MgSO ₄ and evaporated to give 2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a- Tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -2-nitro-propane-1, 3-diol (78 mg) is provided as a beige resin; LC-MS: t _R = 1.17 min, [M + 1] < + > = 500.89.

c) 2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl in acetonitrile (9 ml), TFA (4 ml) and water (0.5 mL) -1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} A solution of -2-nitro-propane-1,3-diol (75 mg, 0.151 mmol) is treated with Zn (200 mg, 3.06 mmol). The suspension is stirred at 65 ° C. for 1 h, after which another portion of Zn (100 mg, 1.53 mmol) is added. Stirring is continued for 45 min at 65 ° C. The mixture was filtered and the filtrate was washed with 2 N aq. Poured over NaOH and extracted three times using DCM. The organic extract is dried over MgSO ₄ and evaporated. After evaporation of the product isolated from a mixture of methanol (9 mL) and 6 N HCl in isopropanol (1 mL), the crude product was prep. Purified by HPLC (Water Symmetry C18, 19 × 50 mm, gradient 95% water (0.5% formic acid) to 95% acetonitrile), 2-amino-2- {2,6-dimethyl-4- [5-((1aS , 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadia Zol-3-yl] -phenoxymethyl} -propane-1, 3-diol hydrochloride (23 mg) is provided as a colorless powder; LC-MS: t _R = 0.89 min, [M + 1] < + > = 470.26; ¹ H NMR (D ₆ -DMSO): δ 8.18 (s br, 3H), 7.69 (s, 2H), 5.47 (s br, 2H), 3.87 (s, 2H), 3.71 (s, 4H), 3.07 ( dd, J = 5.9, 18.8 Hz, 1H), 2.84 (d, J = 18.8 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 6H), 2.08-1.97 (m, 2H), 1.1 1 ( s, 3H), 0.70 (s, 3H).

Example 38

a) in a solution of 3,5-dimethyl-4-hydroxy benzoic acid (158 mg, 0.95 mmol), TBTU (305 mg, 0.95 mmol), DIPEA (0.49 ml, 2.85 mmol) in DMF (2.5 ml) (1aS, 5aR) -N-hydroxy-1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- in DMF (3.5 ml) 4-carboxamidine (200 mg, 0.852 mmol) is added. The resulting suspension is stirred at rt for 2 h. Another portion of 3,5-dimethyl-4-hydroxy benzoic acid (158 mg, 0.95 mmol), TBTU (305 mg, 0.95 mmol) and DIPEA (0.49 ml, 2.85 mmol) was added and further stirred for 30 min This continues. The reaction mixture is immediately prep. Purification by HPLC (Phenomenex Aqua 30x75 mm, 20-95% acetonitrile in water containing 0.5% formic acid) to give the hydroxyamidine ester intermediate (150 mg) as a colorless solid; LC-MS: t _R = 1.04 min, [M + 1] < + > = 385.20.

b) A solution of the hydroxyamidine ester (150 mg, 0.40 mmol) in toluene is stirred at 110 ° C. for 35 h. The solvent is removed under reduced pressure and the residue is prep. Purified by HPLC (Phenomenex Aqua 30x75 mm, 20-95% acetonitrile in water containing 0.5% formic acid) to give 2,6-dimethyl-4- [3-((1aS, 5aR) -1,1, 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-5-yl] -phenol (125 mg) as a colorless solid; LC-MS: t _R = 1.19 min, [M + I] < + > = 367.18; ¹ H NMR (CDCl ₃ ): δ 7.80 (s, 2H), 5.07 (s, 1H), 3.06 (dd, J = 5.9, 18.8 Hz, 1H), 2.89 (d, J = 18.8 Hz, 1H), 2.42 (s, 3H), 2.33 (s, 6H), 1.98-1.90 (m, 2H), 1.15 (s, 3H), 0.78 (s, 3H).

Examples 39-43

((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl) in isopropanol (1 mL) To a solution of-[1,2,4] oxadiazol-5-yl] -phenol (10 mg, 0.027 mmol), the corresponding alkylating agent (as bromine, chlorine, or mesylate) (0.135 mmol) and 2 N aq . NaOH (0.2 ml) is added. The reaction mixture is mixed at 65 ° C for 10 h. The reaction mixture was prep. Purification by HPLC (Waters XTerra Prep MS C18 19 × 50 mm 5 um, 80% to 5% water (0.85% NEt 2) / acetonitrile) gives the desired product as a colorless lyophilisate. In the case of Example 43, the reaction mixture is mixed at 80 ° C. for 10 h. For deprotection of the diol component, the product obtained after purification is dissolved in 1 ml CH 3 COOH / H 2 O 8: 2 and left at rt for 2 h before prep. It is purified once more by HPLC.

Example 44

a) 3-trifluoromethylbenzonitrile in an ice-cooled suspension of K-tert-butylate (22.44 g, 200 mmol) and hydroxylamine hydrochloride (8.34 g, 120 mmol) in methanol (250 ml) 6.84 g, 40 mmol) is added. The mixture is refluxed for 2.5 h, the solvent is removed under reduced pressure, and the residue is dissolved in water. The solution is extracted twice using EA. The organic extract was dried over Na ₂ SO ₄ , evaporated and dried under high vacuum to give N-hydroxy-3-trifluoromethyl-benzamidine (8.1 g) as a white solid, LC-MS: t _R = 0.54 min, [M + 1] + = 205.18.

b) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopro-pa [a] pentalene-4- in DMF (7 ml) To a solution of carboxylic acid (450 mg, 2.03 mmol), TBTU (715 mg, 2.23 mmol) and DIPEA (863 mg, 6.68 mmol), N-hydroxy-3-trifluoromethyl-benzamidine (455 mg, 2.23 mmol) is added and the mixture is stirred at rt for 1.5 h. Formic acid (1.2 ml) is added and the mixture is prep. Purified by HPLC (Grom-Sil 120 ODS-4-HE, 30x75 mm, 10 μιη, 20-95% acetonitrile in water containing 0.5% formic acid), (1aS, 5aR) -1,1, 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid N- (N-hydroxy-3-trifluoromethylbenzamidine) ester (520 mg) as a colorless lyophilisate; LC-MS: t _R = 1.12 min, [M + 1] < + > = 409.20.

c) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid N- (N in toluene Solution of hydroxy-3-trifluoromethylbenzamidine) ester (480 mg) was refluxed for 7 days and then the solvent was removed under reduced pressure. The residue was purified by CC on silica gel eluting with DCM to afford 3- (3-trifluoromethyl-phenyl) -5-((1aS, 5aR) -1,1,2-trimethyl-1 , 1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole (360 mg) is provided as a pale yellow solid; LC-MS: t _R = 1.26 min, [M + 1] < + > = 391.2; ¹ H NMR (CDCl ₃ ): δ 8.39 (s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H ), 3.12 (dd, J = 6.4, 18.8 Hz, 1H), 2.95 (d, J = 18.8 Hz, 1H), 2.45 (s, 3H), 2.02- 1.93 (m, 2H), 1.15 (s, 3H) , 0.77 (s, 3 H).

Example 45

a) To an ice-cooled solution of H 2 SO 4 (150 ml) in water (250 ml) 2-ethyl-6-methylaniline (15.0 g, 111 mmol) is added. The solution was treated with ice (150 g), followed by dropwise addition of a solution of NaNO2 (10.7 g, 155 mmol) in water (150 ml) and ice (50 g). The mixture is stirred at 0 ° C. for 1 h. 50% aq. H 2 SO 4 (200 ml) is added and stirring is continued at rt for 18 h. The mixture is extracted using DCM and the organic extracts are dried over MgSO ₄ and evaporated. The crude product was purified by CC on silica gel eluting with 9: 1 heptane: EA to give 2-ethyl-6-methyl-phenol (8.6 g) as scarlet oil; LC-MS: t _R = 0.89 min; ¹ H NMR (CDCl ₃ ): δ 7.03-6.95 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 4.60 (s, 1H), 2.64 (q, J = 7.6 Hz, 2H), 2.25 (s, 3H), 1.24 (t, J = 7.6 Hz, 3H).

b) A solution of 2-ethyl-6-methyl-phenol (8.40 g, 61.7 mmol) and hexamethylene tetraamine (12.97 g, 92.5 mmol) in acetic acid (60 ml) and water (14 ml) to 115 ° C. Heated. Water is distilled at 117 ° C. and collected using Dean-Stark apparatus. The water separator is then replaced with a reflux condenser and the mixture is refluxed for 3 h. The mixture is cooled to rt, diluted with water (100 ml) and extracted using EA. The organic extract is sat. aq. Rinsed with NaHCO ₃ , dried over MgSO ₄ and evaporated. The remaining solid is dissolved in EA and treated with heptane to initiate crystallization. The solid material was collected and dried to give 3-ethyl-4-hydroxy-5-methyl-benzaldehyde (3.13 g) as a colorless crystalline powder; ¹ H NMR (CDCl ₃ ): δ 9.83 (s, 1H), 7.58-7.53 (m, 2H), 5.30 (s br, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.32 (s, 3H ), 1.28 (t, J = 7.6 Hz, 3H).

c) Trifluoromethanesulphonic in an ice-cooled solution of 5-ethyl-4-hydroxy-3-methylbenzaldehyde (10.0 g, 60.9 mmol) in DCM (50 ml) and pyridine (15 ml) Acid anhydride (18.9 g, 67 mmol) is added over 20 min. Upon completion of the addition, the ice bath is removed and the reaction is stirred at further rt for 2 h. The mixture is diluted with DCM (150 ml), rinsed three times with water, dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 9: 1 heptane: EA to give trifluoro-methanesulphonic acid 2-ethyl-4-formyl-6-methyl-phenyl ester ( 10.75 g) as a pale yellow oil; LC-MS: t _R = 1.07 min; ¹ H NMR (CDCl ₃ ): δ 9.98 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 2.85 (q, J = 10.1 Hz, 2H), 2.48 (s, 3H), 1.30 (t, J = 10.2 Hz, 3H).

d) To a stirred solution of said triflate (10.7 g, 36.1 mmol) in dry DMF (75 ml) under triethylamine (7.3 g, 72.2 mmol), methyl acrylate (31.1 g, 361 mmol), DPPP under nitrogen (819 mg, 1.99 mmol) and Pd (OAc) ₂ (405 mg, 1.81 mmol) are added sequentially. The mixture was stirred at 115 ° C. for 5 h, cooled to rt, diluted with diethyl ether (350 ml) and 1 N aq. Rinse twice with HCl and sat. aq. Rinse once with NaHCO ₃ solution. The organic extract is dried over MgSO ₄ , filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 19: 1 heptane: EA to give 3- (2-ethyl-4-formyl-6-methyl-phenyl) -acrylic acid methyl ester (5.93 g) as a colorless solution; LC-MS: t _R = 0.99 min.

e) methanol (140 ml) and 2 N aq. A suspension of 3- (2-ethyl-4-formyl-6-methyl-phenyl) -acrylic acid methyl ester (5.93 g, 25.53 mmol) in NaOH (45 ml) is stirred at rt for 1 h. Methanol is evaporated and the aqueous solution is extracted twice with DCM. The aqueous layer was 37% aq. Acidified using HCl. The precipitate that forms is collected, rinsed with water and dried. The product was further purified by recrystallization from EA (100 mL) to give 3- (2-ethyl-4-formyl-6-methyl-phenyl) -acrylic acid (4.2 g) as yellow crystals; LC-MS: t _R = 0.87 min.

f) Pd in a solution of 3- (2-ethyl-4-formyl-6-methyl-phenyl) -acrylic acid (2.75 g, 12.6 mmol) and DIPEA (1.8 g, 13.8 mmol) in ethanol (80 mL) / C (275 mg, 10% Pd, humidified with 50% water) is added. The mixture is stirred at rt for 16 h under 1 atm of H 2. The catalyst is filtered off and the filtrate is concentrated. The residue is dissolved in EA and 2 N aq. HCl, then 1 N aq. Rinsed with HCl and brine. The organic extract was dried over Na ₂ SO ₄ , filtered and evaporated to give 3- (2-ethyl-4-hydroxymethyl-6-methyl-phenyl) -propionic acid (2.8 g) as a white solid. ; LC-MS: t _R = 0.76 min.

g) A solution of 3- (2-ethyl-4-hydroxymethyl-6-methyl-phenyl) -propionic acid (2.8 g, 12.6 mmol) in acetic acid (50 ml) was MnO 2 (3.9 g, 45.4 mmol). The resulting mixture was stirred at 80 ° C for 4 h. The mixture is filtered and the filtrate is concentrated. The crude product was purified by CC on silica gel eluting with DCM to afford 3- (2-ethyl-4-formyl-6-methyl-phenyl) -propionic acid (1.76 g) as a beige solid Provided as; LC-MS: t _R = 0.86 min.

h) 3- (2-ethyl-4-formyl-6-methyl-phenyl) -propionic acid (1.67 g, 7.58 mmol) and hydroxylamine hydrochloride (780) in 1-methyl-2-pyrrolidone mg, 1 1.36 mmol) is heated to 80 ° C. for 30 min in microwave (300 W, active cooling during irradiation). The reaction mixture is diluted with diethyl ether and rinsed with water and brine. The organic extract was dried over Na ₂ S0 ₄ , filtered and evaporated to give 3- (4-cyano-2-ethyl-6-methyl-phenyl) -propionic acid (1.55 g) as a beige solid. ; LC-MS: t _R = 0.89 min, ¹ H NMR (D ₆ -DMSO): δ 12.25 (s, 1H), 7.45 (s, 2H), 2.91 -2.84 (m, 2H), 2.67-2.59 (m, 2H), 2.35-2.30 (m, 5H), 1.14 (t, J = 7.6 Hz, 3H).

i) potassium tert. Butoxide (2.71 g, 24.1 mmol) is carefully dissolved in methanol (25 mL). To this solution, hydroxylamine hydrochloride (1.44 g, 20.7 mmol) and 3- (4-cyano-2-ethyl-6-methyl-phenyl) -propionic acid (1.50 g) dissolved in methanol (7.5 mL) , 6.90 mmol) is added. The mixture is refluxed for 8 h and the solvent is evaporated. The residue is 2 N aq. It is dissolved in HCl and extracted using EA. The pH of the aqueous phase is sat. aq. The pH is adjusted to 5 by the addition of NaHCO ₃ and the mixture is extracted three times using EA. The combined organic extracts were dried over Na ₂ S0 ₄ , filtered, evaporated and dried to give 3- [2-ethyl-4- (N-hydroxycarbamidomiyl) -6-methyl-phenyl]- Propionic acid (1.4 g) is provided as a white solid; LC-MS: t _R = 0.60 min, [M + 1] < + > = 251.17.

j) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene-4-carboxylic acid in DMF (3 mL) To a solution of (270 mg 1.22 mmol), TBTU (390 mg, 1.22 mmol) and DIPEA (518 mg, 4.0 mmol) are added. The reaction mixture was stirred at rt for 5 min, then 3- [2-ethyl-4- (N-hydroxycarbamidomiyl) -6-methyl-phenyl] -propionic acid in DMF (2 mL) 305 mg, 1.22 mmol) is added. Stirring is continued at rt for 1 h. The mixture is diluted with formic acid (0.5 ml) and acetonitrile (5 ml), prep. Isolated by HPLC (Grom-Sil 120 ODS-4-HE, 30 × 75 mm, 10 μm, 10-95% acetonitrile in water containing 0.5% formic acid), (1aS, 5aR) -1,1, 2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid N- (3-ethyl-5-methyl-4- (2-carboxy-ethyl ) -N-hydroxybenzamidine) ester (260 mg) is provided as a white solid; LC-MS: t _R = 1.05 min, [M + 1] + = 455.32.

k) (1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentane-4-carboxylic acid in toluene (10 mL) A suspension of N- (3-ethyl-5-methyl-4- (2- (hydroxy-carboxy) -ethyl) -N-hydroxybenzamidine) ester (255 mg, 0.561 mmol) was 24 h up to 85 ° C. Then heated at 105 ° C. for 3 days. The mixture is cooled to rt and the solvent is evaporated. The residue is dissolved in DMF and prep. Separated by HPLC (Grom-Sil 120 ODS-4-HE, 30 × 75 mm, 10 μm, 70-100% acetonitrile in water containing 0.5% formic acid), 3- {2-ethyl-6-methyl -4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl)- [1,2,4] oxadiazol-3-yl] -phenyl} -propionic acid (150 mg) is provided as a white crystalline solid; LC-MS: t _R = 1.19 min, [M + 1] < + > = 437.28; ¹ H NMR (D ₆ -DMSO): δ 12.26 (s, 1H), 7.64 (s, 1H), 7.63 (s, 1H), 3.08 (dd, J = 6.4, 19.3 Hz, 1H), 2.94-2.89 ( m, 2H), 2.84 (d, J = 18.2 Hz, 1H), 2.69 (q, J = 7.6 Hz, 2H), 2.41 (s, 3H), 2.39-2.33 (m, 5H), 2.05 (d, J = 5.8 Hz, 1H), 1.99 (t, J = 5.8 Hz, 1H), 1.19 (t, J = 7.6 Hz, 3H), 1.1 1 (s, 3H), 0.70 (s, 3H).

Examples 46 and 47

3- {2-ethyl-6-methyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3 in DMF (0.5 mL) To a solution of -thia-cyclopropa [a] pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenyl} -propionic acid (9 mg, 20 μmol), TBTU (7 mg, 22 μmol) and DIPEA (9 mg, 66 μmol) are added. The mixture is stirred at rt for 5 min before the appropriate amine (100 μmol) is added. Stirring is continued at rt for 1 h. The mixture was treated with formic acid (25 μL), diluted with acetonitrile (0.5 mL) and prep. Separated by HPLC (Waters Symmetry C18 19 × 50 mm 5 μm, 20-100% acetonitrile in water containing 0.5% formic acid) to provide the target amide as a colorless resin.

Example 48 GTPγS Assay to Determine EC ₅₀ Values

GTPγS binding assays are performed in 96 well microtiter plates (Nunc, 442587) in a final volume of 200 μl using membrane preparation of CHO cells expressing recombinant human S1 P1 receptor. Analytical conditions were 20 mM Hepes (Fluka, 54461), 100 mM NaCl (Fluka, 71378), 5 mM MgCI2 (Fluka, 63064), 0.1% BSA (Calbiochem, 126609), 1 μM GDP (Sigma, G-7127), 2.5% DMSO (Fluka, 41644), 50 pM ³⁵ S-GTPγS (Amersham Biosciences, SJ 1320). pH is 7.4. Test compounds are dissolved, diluted in 100% DMSO and pre-incubated for ³⁰ min in 150 μl of the above assay buffer in the absence of ³⁵ S-GTPγS. After addition of 50 μl of ³⁵ S-GTPγS, the analytes are incubated for 1 h at room temperature. The assay was terminated by transferring the reaction mixture to a multiscreen plate (Millipore, MAHFC1H60) using a Packard Biosciences cell harvester, the plate was ice-cold 10 mM Na ₂ HPO ₄ / NaH ₂ PO ₄ (70% / 30%) Rinse, dry, bottom sealed and 25 μl of MicroScint20 (Packard Biosciences, order # 6013621) is added and top closed. Membrane-bound ³⁵ S-GTPγS is measured using PackCount Biosciences TopCount.

EC ₅₀ is the concentration of antagonist that induces 50% of maximal specific ³⁵ S-GTPγS binding. Specific binding is determined by subtracting non-specific binding from maximal binding. Maximum binding is the amount of cpm bound to the multiscreen plate in the presence of 10 μM S1P. Non-specific binding is the amount of binding in the absence of antagonist in the analyte.

Table 1 below shows the EC 5 _O values of some compounds of the present invention. EC ₅₀ values were determined according to the above method.

Table 1.

Example 49 Assessment of In Vivo Efficacy

The efficacy of the compound of formula (I) is assessed by measuring circulating lymphocytes after oral administration of 3-30 mg / kg of compound of formula (I) to male rats of normal blood pressure. Animals are housed under climate-controlled conditions with a 12 h-light / dark cycle and have free access to conventional rat food and drinking water. Blood is collected before drug administration and 3, 6, and 24 hours after drug administration. All blood is tested for blood using the Advia Hematology system (Bayer Diagnostics, Zurich, Switzerland).

All data are expressed as mean ± SEM. Statistical analysis is performed by analyzing the deviation (ANOVA) using Statistica (StatSoft) and Student-Newman-Keuls procedure for multiple comparisons. The random hypothesis is rejected when p <0.05.

As in the examples, Table 2 compares the effect of 10 mg / kg of the two compounds of the present invention on lymphocyte counts after 6 h after oral administration to male rats of normal blood pressure, compared to a group of animals treated with vehicle only. Shows.

Table 2:

The present invention relates to novel thiophene derivatives of formula (I), their preparation and use as pharmaceutically active compounds. The compound functions in particular as an immunosuppressive agent. Wherein ring A represents oxadiazole and other substituents are as defined in the detailed description.

Claims (20)

The following enantiomers, such as thiophenes of formula (I) and optically pure enantiomers, racemates, diastereomers, mixtures of diastereomers, diastereomeric racemates, and mixtures of diastereomeric racemates Compounds selected from the group consisting of mixtures of isomers and coordination isomers such as salt and solvent complexes of these compounds, and morphological forms; Formula (I) here Ring A represents R ¹ is hydrogen, C _{1 -5} - alkyl, C _{1 -5} - represents a alkoxy, or halogen; R ² is hydrogen, C _{1 -5} - alkyl, C _{1 -5} - alkoxy, trifluoromethyl, trifluoro-Romero represents ethoxy, or halogen; R ³ is hydrogen, hydroxy -C _{1 -5-alkyl,} 2,3-dihydroxy-propyl, di- (hydroxy -C _1-5 - alkyl) -C _{1 -5-alkyl,} -CH ₂ - ( _{^{CH 2) k -NR 31 R 32}} , ( azetidine-3-carboxylic acid) -1-yl-methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2- [ (azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(azetidine -3 -carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, (pyrrolidine-3-carboxylic acid pi) -1-yl -methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C 1-5- alkyl-ester) -1-yl-methyl, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-3-carboxylic acid C _{1 - 5-alkylester)} -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(par Pyrrolidine-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [(pi pyrrolidine- 3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] _{-propyl, -CH 2 - (CH 2)} n -COOH, -CH 2 - (CH 2) n -CONR 31 R 32, -CO-NHR 31, - (CH2) nCH (OH) - CH2-NR 31 R 32, hydroxy, C _{1 -5-alkyl,} -C _{1 -5;} fluoro-alkoxy, hydroxy -C _{2 -5-alkoxy,} di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, _{2-hydroxy-3-methoxy-propoxy, -OCH 2 - (CH 2)} m -NR ³¹ R ³² , 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C _{1 -5} -alkyl) -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1-yl _{-propoxy, 3- [4- (C 1 -5} - Al ) -Piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2-[(azetidine-3-carboxylic acid C _1-5 -alkylester) 1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkyl} ester) 1- yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1 -Yl] -ethoxy, 2-[(2-hydroxy-pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -ethoxy , 3 - [(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 [(pyrrolidone-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3- [ (pie Naphthyridin-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy Hydroxy-pyrrolidin) -1-yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxy methyl-propoxy, -0-CH ₂ -CONR ³¹ R ^32, 3-carbamoyl-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxy-ethyl carboxamide Barmoyl) propoxy, -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , 3-[(azetidin-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3- [ (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(pi pyrrolidine- 2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-2-car Acids C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 2-hydroxy- 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1 -yl-propoxy, 2-hydroxy-3-piperazine- 1-yl-propoxy, 2-hydroxy-3- [4- (C _1-5 -alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2- Hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, -NR ³¹ R ³² , -NHCO-R ³¹ , -CH _{2- (CH 2) k -NHSO 2 R} 33, - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH ₂ -NHSO ₂ R ³³ , -CH _2- (CH ₂ ) _k -NHCOR ³⁴ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m -NHCOR ^34, or _{-OCH 2 -CH (OH) -CH 2} - NHCOR represents ^34; R ³¹ is hydrogen, methyl, ethyl, 1-propyl, 2-propyl, 2-hydroxyethyl, 2-hydroxy-1-hydroxymethyl-ethyl, 2-C _{1 -5-alkoxyethyl,} 3-hydroxy propyl, 3-C _{1 -5} - alkoxy-propyl, 2-aminoethyl, 2- (C _{1 -5} - alkylamino) ethyl, 2- (di - (C _{1 -5} - alkyl) amino) ethyl, carboxymethyl, C _{1 -5} - alkyl carboxymethyl, 2-carboxyethyl, or 2- (C _{1 -5} - alkyl carboxy) represents ethyl; R ³² represents hydrogen, methyl, or ethyl; R ³³ represents methyl, ethyl, propyl, isopropyl, butyl, 2-hydroxyethyl, 2-methoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, or dimethylamino; R ³⁴ represents hydroxymethyl, hydroxyethyl, aminomethyl, methylaminomethyl, dimethylaminomethyl, aminoethyl, 2-methylamino-ethyl, or 2-dimethylamino-ethyl; k represents the integer 1, 2, or 3; m represents an integer of 1 or 2; n represents O, 1, or 2; R ⁴ is hydrogen, C _{1 -5} - represents an alkyl, or halogen. The method of claim 1, wherein, R ³ is hydrogen, hydroxy -C _{1 -5-alkyl,} 2,3-dihydroxy-propyl, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkyl , -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1 -yl-methyl, (azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl -methyl 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, (pyrrolidine-3-pi carboxylic acid) -1-yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi) -1-yl-methyl, (pi pyrrolidine-2-carboxylic acid C _{1 -5-alkylester)} -1-yl-methyl, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethyl, 2 - [(pi pyrrolidine -3 - carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 2 - [(carboxymethyl-2-pyrrolidone Acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidine-3-carboxylic acid pi) - 1- yl] -propyl, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl ] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] _{-propyl, -CH 2 - (CH 2)} n -CONR 31 R 32, -CO-NHR _{^{31, - (CH 2) n}} CH (OH) -CH 2 -NR 31 R 32, hydroxy, C _{1 -5} - alkoxy, fluoro -C _{1 -5} - alkoxy, hydroxy, -C _{2 -5} - alkoxy , di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH ₂ - ( CH ₂ ) _m- NR ³¹ R ³² , 2-pyrrolidin-1-yl-ethoxy, 3-pyrrolidin-1-yl-propoxy, 2-piperazin-1-yl-ethoxy, 2- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -ethoxy, 2- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3 piperazin-1-yl-propoxy, 3- [4- (C _{1 - 5} -alkyl) -piperazin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl- ethoxy, 3-morpholine-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2- [(azetidine-3-carboxylic acid C _{1 -5-} alkylester) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkyl} ester) 1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkyl} ester ) -1-yl] -ethoxy, 2-[(2-hydroxy-pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -Ethoxy, 3-[(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(azetidin-3-carboxylic acid C _1-5 -alkylester) -1-yl] -propoxy , 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3-[( Pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2 -Hydroxy-pyrrolidin) -1-yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2- hydroxymethyl-propoxy, -0-CH ₂ -CONR ³¹ R ^32, 3-carbamoyl-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxy Ethylcarbamoyl) propoxy, -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , 3-[(azetidine-3-carboxylic acid) -1-yl] -2-hydroxypropoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid) -1 - yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone Din-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3-[(pyrroli -2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 2 -Hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-pyrrolidin-1 -yl-propoxy, 2-hydroxy-3 -Piperazin-1 -yl-propoxy, 2-hydroxy-3- [4- (Ci_ ₅ -alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4 -(2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3-morpholin-4-yl-propoxy, -NR ³¹ R ³² , -NHCO-R ³¹ , _{-CH 2 - (CH 2) k} -NHSO 2 R 33, - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, - _{OCH 2 -CH (OH) -CH 2} -NHSO 2 R 33F, -CH 2 - (CH 2) k -NHCOR 34, - (CH 2) n CH (OH) -CH 2 -NHCOR 34, -OCH 2 - (CH ₂ ) _m -NHCOR ³⁴ , or -OCH ₂ -CH (OH) -CH ₂ -NHCOR ³⁴ , wherein R ³¹ , R ³² , R ³³ and R ³⁴ are as defined in claim 1. Compound. The compound according to claim 1 or 2, wherein the compound represented by formula (I) is 1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] phen. A compound characterized by constituting the (1aR, 5aS) -isomer of a thylene derivative. A compound according to claim 1 or 2, wherein the compound represented by formula (I) is 1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] phen A compound characterized by constituting the (1aS, 5aR) -isomer of a thylene derivative. The compound of any one of claims 1 to 4, wherein the compound represented by the formula (I) constitutes a 5-thiophen-2-yl- [1,2,4] oxadiazole derivative. compound. The compound of any one of claims 1 to 4, wherein the compound represented by the formula (I) constitutes a 3-thiophen-2-yl- [1,2,4] oxadiazole derivative. compound. 7. The compound of claim ¹ , wherein R ¹ , R ² , and R ⁴ represent hydrogen. 7. The compound of claim 1, wherein R ¹ represents hydrogen and R ² and R ⁴ represent a methyl group. 7. The compound of claim 1, wherein R ¹ represents hydrogen, R ² represents a methyl group, and R ⁴ represents an ethyl group. 7. The compound of claim 1, wherein R ¹ represents hydrogen, R ² represents a methoxy group and R ⁴ represents chlorine. The method according to any one of claims 1 and 3 to 10, wherein, R ³ is hydrogen, hydroxy, -C _1-5 - alkyl, 3-di-hydroxypropyl, di- (hydroxy -C _{1 -5} -alkyl) -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1 -yl-methyl, (azetidine-3-carboxylic acid C _{1 -5} -alkyl ester) -1 -yl-methyl, 2-[(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2-[(azetidine-3-carboxylic acid C-ι-5-alkylester ) -1-yl] -ethyl, 3- [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl ] -propyl, (pyrrolidine-3-carboxylic acid pi) -1 -yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1 -yl-methyl, (pyrrolidine-2-pi carboxylic acid) -1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] - ethyl, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1 ] -Ethyl, 2 - [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl , 3-[(pyrrolidin-3-carboxylic acid) -1-yl] -propyl, 3- [(pyrrolidine-3-carboxylic acid C _1-5 -alkylester) -1-yl] -propyl, 3- [(pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, -CH ₂ - ( _{CH 2) n -COOH, -CH 2} - (CH 2) n -CONR 31 R 32, -CO-NHR 31, - (CH2) nCH (OH) - CH2-NR 31 R 32, hydroxy, C _{1 - 5-alkoxy,} fluoro -C _{1 -5-alkyl,} hydroxy -C _{2 -5-alkoxy,} di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH _2- (CH ₂ ) _m -NR ³¹ R ³² , 2-pyrrolidin-1 -yl-ethoxy, 3-pyrroli Dean-1 - yl-propoxy, 2-piperazin-1 - yl-ethoxy, 2- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -ethoxy, 2- [4 -(2-hydroxy-ethyl) -p 1-yl] -ethoxy, 3-piperazin-1 - yl-propoxy, 3- [4- (C _{1 -5-alkyl)} -piperazin-1 - yl] -propoxy, 3- [ 4- (2-Hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy, 2-[( azetidine-3-carboxylic acid) -1-yl] -ethoxy, 2- [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(pi pyrrolidine 3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2- [(pyrrolidine pie - 2-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(2-hydroxy- Pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -ethoxy, 3-[(azetidine-3-carboxylic acid) -1-yl ] -propoxy, 3- [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] - Propoxy, 3-[(pi Pyrrolidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid) -1-yl] -propoxy, 3 - [(pyrrolidone -2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy-pi pyrrolidine) -1-yl] -propoxy, 3 - [(3 Hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -0-CH ₂ -CONR ³¹ R ³² , 3-carbamoyl -propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxyethyl carbamoyl) _{propoxy, -OCH 2 -CH (OH) -CH} 2 -NR 31 R ^32, 3 - [(azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] - 2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid) -1 -yl] -propoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid C _1-5-alkyl ester) -1-yl] -propoxy, 2-hydroxy-3 - [(pi roll Naphthyridin-2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3- [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2- Hydroxy-3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -prop Foxy, 2-hydroxy-3-pyrrolidin-1-yl-propoxy, 2-hydroxy-3-piperazin-1 -yl-propoxy, 2-hydroxy-3- [4- (C _{1 -5} -alkyl) -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-hydroxy Oxy-3-morpholin-4-yl-propoxy, or -NR ³¹ R ³² , -NHCO-R ³¹ , wherein R ³¹ and R ³² are as defined in claim 1. The method according to any one of claims 1 to 10, R ³ is hydroxy _-5 -C ₂ - alkoxy, di- (hydroxy -C _{1 -5-alkyl)} -C _{1 -5-alkoxy,} 1-glyceryl Reyl, 2-glyceryl, 2-hydroxy-3-methoxy-propoxy, -OCH _2- (CH ₂ ) _m -NR ³¹ R ³² , 2-pyrrolidin-1 -yl-ethoxy, 3- pie pyrrolidine-1 - yl-propoxy, 2-piperazin-1 - yl-ethoxy, 2- [4- (C _{1 -5-alkyl)} -piperazin-1-yl] -ethoxy, 2 [4- (2-hydroxy-ethyl) -piperazin-1-yl] -ethoxy, 3-piperazin-1 - yl-propoxy, 3- [4- (C _{1 -5-alkyl)} -piperazin Razin-1-yl] -propoxy, 3- [4- (2-hydroxy-ethyl) -piperazin-1-yl] -propoxy, 2-morpholin-4-yl-ethoxy, 3-mor morpholine-4-yl-propoxy, 2 - [(azetidine-3-carboxylic acid) - 1-yl] -ethoxy, 2- [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1 yl] -ethoxy, 2- [(pyrrolidone-3-carboxylic acid) -1-yl] -ethoxy, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl ] -Ethoxy, 2-[( The pyrrolidine-2-carboxylic acid) -1-yl] -ethoxy, 2- [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethoxy, 2 - [(2 -Hydroxy-pyrrolidin) -1-yl] -ethoxy, 2-[(3-hydroxy-pyrrolidin) -1-yl] -ethoxy, 3-[(azetidine-3-carboxylic acid) -1-yl] -propoxy, 3-[(azetidine-3-carboxylic acid C _1-5 -alkylester) -1-yl]-propoxy, 3-[(pyrrolidine-3-carboxylic acid) -1 -yl] -propoxy, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid) -1 yl] -propoxy, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 3 - [(2-hydroxy-pi pyrrolidine) -1 Yl] -propoxy, 3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-amino-3-hydroxy-2-hydroxymethyl-propoxy, -0-CH ₂ -CONR ³¹ R ^32, 3- carbamoyl-propoxy, 3- (C _{1 -5-alkyl-carbamoyl)} propoxy, 3- (2-hydroxy Ethylcarbamoyl) _{propoxy, -OCH 2 -CH (OH) -CH2} -NR 31 R 32, 3 - [( azetidine-3-carboxylic acid) -1-yl] -2-hydroxy-propoxy, 3- [(azetidine-3-carboxylic acid C _{1 -5} - alkylester) -1-yl] -2-hydroxy-propoxy, 2-hydroxy-3- [(pyrrolidone-3-carboxylic acid) -1-yl ] -propoxy, 2-hydroxy-3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy-3 - [(pi pyrrolidine 2-carboxylic acid) -1-yl] -propoxy, 2-hydroxy-3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propoxy, 2-hydroxy Hydroxy-3-[(2-hydroxy-pyrrolidin) -1-yl] -propoxy, 2-hydroxy-3-[(3-hydroxy-pyrrolidin) -1-yl] -propoxy , 2-hydroxy-3-pyrrolidin-1 -yl-propoxy, 2-hydroxy-3-piperazin-1 -yl-propoxy, 2-hydroxy-3- [4- (C _{1- 5-alkyl)} -piperazin-1-yl] -propoxy, 2-hydroxy-3- [4- (2-hydroxy- Butyl) -piperazin-1-yl] - represents a propoxy R ³¹ and R ³² is characterized by as hereinbefore defined in claim 1-propoxy, or 2-hydroxy-3-morpholine-4-yl Compound. The method according to any one of claims 1 and 3 to 10, wherein, R ³ is hydroxy -C _{1 -5-alkyl,} 2,3-dihydroxy-propyl, di- (hydroxy -C _{1 -5-alkyl} ) -C _{1 -5-alkyl, -CH 2 - (CH 2)} k -NR 31 R 32, ( azetidine-3-carboxylic acid) -1 -yl-methyl, (azetidine-3-carboxylic acid C _{1 -5} - alkylester) -1-yl-methyl, 2- [(azetidine-3-carboxylic acid) -1-yl] -ethyl, 2 - [(azetidine-3-carboxylic acid C _{1 -5-alkyl} ester) -1 -yl] -ethyl, 3 - [(azetidine-3-carboxylic acid) -1-yl] -propyl, 3 - [(azetidine-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl , (pi pyrrolidine-3-carboxylic acid) -1 -yl-methyl, (pyrrolidine-3-carboxylic acid pi C _{1 -5-alkylester)} -1 -yl-methyl, (pyrrolidine-2-carboxylic acid pi) - 1-yl-methyl, (pyrrolidine-2-carboxylic acid pi C _{1 -5-alkylester)} -1-yl-methyl, 2 - [(pyrrolidone-3-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] - Butyl, 2- [(pyrrolidone-2-carboxylic acid) -1-yl] -ethyl, 2 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -ethyl, 3 - [(pyrrolidone-3-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-3-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, 3 - [( pyrrolidone-2-carboxylic acid) -1-yl] -propyl, 3 - [(pyrrolidone-2-carboxylic acid C _{1 -5-alkylester)} -1-yl] -propyl, -CH ₂ - (CH ₂ ) _n -COOH, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CO-NHR ³¹ , or-(CH ₂ ) _n CH (OH) -CH ₂ -NR ³¹ R ³² , and R ³¹ And R ³² is as defined in claim 1. The method according to any one of claims 1 to 10, R ³ is a di- (hydroxy -C _{1 -5-alkyl)} -C _1-5 - alkoxy, 1-glyceryl, -OCH ₂ - (CH _{2) m-} NR ³¹ R ³² , -0-CH ₂ -CONR ³¹ R ³² , or -OCH ₂ -CH (OH) -CH ₂ -NR ³¹ R ³² , and R ³¹ represents methyl or 2-hydroxyethyl R ³² represents hydrogen. The compound of any one of claims 1 and 3 to 10, wherein R ³ is -CH _2- (CH ₂ ) _n -COOH, -CH _2- (CH ₂ ) _n -CONR ³¹ R ³² , -CH _{2- (CH 2) k -NHSO 2 R} 33, - (CH 2) n CH (OH) -CH 2 -NHSO 2 R 33, -OCH 2 - (CH 2) m -NHSO 2 R 33, -OCH 2 -CH (OH) -CH ₂ -NHSO ₂ R ³³ , -CH _2- (CH ₂ ) _k -NHCOR ³⁴ ,-(CH ₂ ) _n CH (OH) -CH ₂ -NHCOR ³⁴ , -OCH _2- (CH ₂ ) _m- NHCOR ³⁴ , or -OCH ₂ -CH (OH) -CH ₂ -NHCOR ³⁴ , wherein R ³¹ , R ³² , R ³³ and R ³⁴ are as defined in claim 1. A compound of claim 1 selected from the group consisting of: 4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[ 1,2,4] oxadiazol-3-yl] -phenol, 2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol, 1- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol, (2S) -3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene -4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, (2R) -3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene -4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, 1-methoxy-3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] phen Talen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol, 2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol, 3- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalen-4-yl )-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1 -ol, Dimethyl- (2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine, Dimethyl- (2- {4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -amine, 2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-3-yl] -phenol, 2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethanol, 1-{2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-2-ol,  (2S) -3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, (2R) -3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propane-1,2-diol, 1-{2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -3-methoxy-propan-2-ol, 2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol, 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propan-1-ol, (2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -dimethyl-amine, 3- [3,5-dimethyl-4- (2-pyrrolidin-1-yl-ethoxy) -phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole, 4- (2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -ethyl) -morpholine, 3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamine, (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -methyl-amine, (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -dimethyl-amine, 2- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3- thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamino) -ethanol, 3- [3,5-dimethyl-4- (3-pyrrolidin-1 -yl-propoxy) -phenyl] -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazole, (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -propyl-amine, 2- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3- thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propylamino) -propane-1,3-diol, N _1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -ethane-1,2-diamine, 1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-2-carboxylic acid, 1- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -pyrrolidine-3-carboxylic acid, 2- [4- (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia- Cyclopropa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -piperazin-1-yl] -ethanol, 2-amino-2- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-S-thia-cycloprop Pa [a] pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxymethyl} -propane-1,3-diol, (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl) -isopropyl-amine, (3- {2,6-dimethyl-4- [5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazol-3-yl] -phenoxy} -propyl)-(2-ethoxy-ethyl) -amine, 2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] pentalene- 4-yl)-[1,2,4] oxadiazol-5-yl] -phenol, 2- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -ethanol, 1- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propan-2-ol, 3- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol, 3- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxy} -propane-1,2-diol, 2- {2,6-dimethyl-4- [3-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a] Pentalen-4-yl)-[1,2,4] oxadiazol-5-yl] -phenoxymethyl} -propane-1,3-diol, and 3- (3-trifluoromethyl-phenyl) -5-((1aS, 5aR) -1,1,2-trimethyl-1,1a, 5,5a-tetrahydro-3-thia-cyclopropa [a ] Pental-4-yl)-[1,2,4] oxadiazole. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. 18. A compound or pharmaceutical composition according to any one of claims 1 to 16, or for use as a medicament, characterized in that it is for use as a medicament. 17. A compound according to any one of claims 1 to 16 for use in the prevention or treatment of diseases or disorders associated with an activated immune system. 20. The method of claim 19, further comprising: rejection of a transplant organ selected from kidney, liver, heart and lung; Graft-versus-host disease caused by stem cell transplantation; Autoimmune syndrome selected from rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease and Hashimoto's thyroiditis; And atopic dermatitis, for use in the prevention or treatment of a disease or disorder selected from the group consisting of atopic dermatitis.